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Advanced Drug Delivery Reviews 55 (2003) 667–686
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Pharmacokinetics in the newborn
Jane Alcorn a , *, Patrick J. McNamara b
a
College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, SK, S7 N 5 C9, Canada
b
Division of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA
Received 11 June 2002; accepted 22 January 2003
Abstract
In addition to differences in the pharmacodynamic response in the infant, the dose and the pharmacokinetic processes
acting upon that dose principally determine the efficacy and / or safety of a therapeutic or inadvertent exposure. At a given
dose, significant differences in therapeutic efficacy and toxicant susceptibility exist between the newborn and adult.
Immature pharmacokinetic processes in the newborn predominantly explain such differences. With infant development, the
physiological and biochemical processes that govern absorption, distribution, metabolism, and excretion undergo significant
growth and maturational changes. Therefore, any assessment of the safety associated with an exposure must consider the
impact of these maturational changes on drug pharmacokinetics and response in the developing infant. This paper reviews
the current data concerning the growth and maturation of the physiological and biochemical factors governing absorption,
distribution, metabolism, and excretion. The review also provides some insight into how these developmental changes alter
the efficiency of pharmacokinetics in the infant. Such information may help clarify why dynamic changes in therapeutic
efficacy and toxicant susceptibility occur through infancy.
 2003 Elsevier Science B.V. All rights reserved.
Keywords: Development; Exposure; Human; Infant; Newborn; Pharmacokinetics
Contents
1. Introduction ............................................................................................................................................................................
1.1. Pharmacokinetics as a determinant of plasma concentration and response.............................................................................
2. Absorption..............................................................................................................................................................................
2.1. Gastrointestinal absorption................................................................................................................................................
2.1.1. Gastrointestinal secretions.......................................................................................................................................
2.1.2. Gastrointestinal motility..........................................................................................................................................
2.1.3. Gastrointestinal metabolism and transport ................................................................................................................
2.2. Gastrointestinal first-pass effects .......................................................................................................................................
3. Distribution.............................................................................................................................................................................
3.1. Body composition and tissue perfusion ..............................................................................................................................
3.2. Plasma protein binding .....................................................................................................................................................
4. Elimination .............................................................................................................................................................................
*Corresponding author. Tel.: 11-306-966-6365; fax: 11-306-966-6377.
E-mail address: [email protected] (J. Alcorn).
0169-409X / 03 / $ – see front matter  2003 Elsevier Science B.V. All rights reserved.
doi:10.1016 / S0169-409X(03)00030-9
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4.1. Hepatic clearance .............................................................................................................................................................
4.1.1. Intrinsic clearance ..................................................................................................................................................
4.1.1.1. Cytochrome P450 enzyme-mediated metabolism .........................................................................................
4.1.1.2. Phase II metabolism...................................................................................................................................
4.1.1.3. Consequences of variability in the postnatal maturation of phase I and phase II reactions................................
4.1.2. Hepatic first-pass effects .........................................................................................................................................
4.2. Renal clearance................................................................................................................................................................
4.2.1. Glomerular filtration...............................................................................................................................................
4.2.2. Renal tubular function ............................................................................................................................................
5. Conclusions ............................................................................................................................................................................
References ..................................................................................................................................................................................
1. Introduction
Adult doses, even after adjusted for differences in
body weight, often lead to drastic consequences in
the newborn patient. Functional immaturity of physiological processes and organ function predispose
newborns to exhibit such disparate responses relative
to the adult. With infant maturation, normal development may modify infant response to drug and
toxicant exposures. The full impact of developmental
immaturity, though, still remains unrealized as exemplified by the number of well-documented therapeutic misjudgments that continue even to this day
[1–3]. We may mitigate future misjudgments through
a greater understanding of how development affects
the factors that govern drug and toxicant response in
the newborn and young infant. Such knowledge may
help ensure safe exposures to therapeutic or inadvertent compounds.
Pharmacokinetic and pharmacodynamic processes
contribute to the significant differences in therapeutic
efficacy and toxicant susceptibility observed between
newborns, young infants and adults. With postnatal
development, growth and functional maturation of
the biochemical and physiological factors governing
pharmacokinetics may alter the processes of absorption, distribution, metabolism and excretion. As well,
these developmental changes proceed along a continuum, at different rates and patterns, resulting in
tremendous interindividual variability in infant pharmacokinetics. The dynamic and highly variable
character of postnatal maturation of infant pharmacokinetic and pharmacodynamic processes may
have significant consequences on the way newborns
and infants respond to and deal with drugs.
As its principal goal, this review discusses the
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affects of postnatal development on drug and toxicant pharmacokinetics in the newborn and early
infancy. The article describes the age-dependent
changes in the physiological and / or biochemical
processes governing drug and toxicant pharmacokinetics. The article then extends these observations to discuss how developmental changes may
lead to significant differences in absorption, distribution, metabolism and / or excretion between the
newborn, infant and the adult. Such discussion
should help explain the dynamic changes in therapeutic efficacy and toxicant susceptibility that occur
through infancy.
1.1. Pharmacokinetics as a determinant of plasma
concentration and response
Therapeutic and toxic responses generally correlate well with the plasma concentration of a compound. Because of this correlation, plasma concentrations may best indicate the potential safety and / or
efficacy of the compound in the newborn and young
infant. This presumes that the pharmacological or
toxic response is direct (i.e., related to corresponding
serum concentrations), expected (i.e., similar to adult
response) and quantitatively similar to adults (i.e.,
similar pharmacodynamic parameters). A more difficult situation arises if the pharmacological or toxic
response is indirect (i.e., unrelated to serum concentrations), novel (a function of the developing
neonatal physiology / biochemistry) and quantitatively dissimilar to adults. Whether pharmacodynamic
differences exist between pediatric population groups
and adults is largely unknown. Given this presumption, two factors govern plasma concentrations, the
size of the dose and the pharmacokinetic processes
J. Alcorn, P. J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667–686
of absorption, distribution, metabolism and excretion
acting upon that dose. The following equations
illustrate the influence of dose and pharmacokinetic
processes on plasma concentrations of a compound,
administered as either a multiple oral dose (Eq. (1))
or as a single oral dose (Eq. (2)).
FD
]
t
C¯ 5 ]] (multiple dose)
Cl S
(1)
or
S
S D 2e
Fk a D
Ct 5 ]]] e 2
Vdsk a 2 k ed
Cl S
]
Vd
t
D (single dose)
2sk a td
(2)
where C¯ is the average steady state plasma concentration; F is the bioavailability; D is the dose; t
is the dosing interval; Cl S is the systemic clearance;
Ct is the plasma concentration at any time, t; k a is
the absorption rate constant; k e is the elimination rate
constant and is equal to Cl S /Vd ; Vd is the volume of
distribution; and t is time.
According to Eqs. (1) and (2), larger doses (D)
result in higher plasma concentrations of an administered compound. As well, these equations clearly
illustrate the importance of absorption (indicated in
the F and k a terms), distribution (indicated in the Vd
term), and metabolism and excretion (indicated in
the Cl S and k e terms) as determinants of plasma
concentrations in the newborn and young infant.
Rapid changes in body size and composition, organ
size and function, and maturation of the underlying
physiological and biochemical processes that govern
absorption, distribution, metabolism, and excretion
characterize the immediate postnatal period. These
developmental changes cause major age-related
changes in drug absorption, distribution and elimination (metabolism and excretion), which may have a
significant impact on plasma concentrations and the
resultant exposure outcomes. Additionally, maturation is a dynamic process influenced by a plethora of
genetic and environmental factors. The rate and
pattern of maturation of each pharmacokinetic process may vary greatly among infants. This may result
in marked interindividual variability in pharmacokinetics such that infants of similar age may
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exhibit differences in toxicant susceptibility or therapeutic efficacy.
In general, the combined effects of maturation of
each pharmacokinetic process on the plasma levels
of a given compound are not well understood.
Premature birth (gestational age ,36 weeks) and
underlying pathophysiology further complicate the
relationship between plasma concentrations and response and the age-related changes in pharmacokinetics. Premature infants exhibit more pronounced anatomical and functional immaturity of the
organs involved in pharmacokinetic processes. The
extent to which premature infants differ from the
full-term infant correlates directly with the degree of
prematurity [4]. This enhanced immaturity, as well
as any underlying disease state(s), may impede
normal postnatal development of the processes of
absorption, distribution and elimination. How these
and other factors may contribute to age-dependent
pharmacokinetics in newborns and infants requires
consideration. The proceeding discussion will summarize the available literature on the influence of
postnatal maturation on drug absorption, distribution,
metabolism and excretion principally in the full-term
infant.
2. Absorption
Age-related differences in absorption relate to
developmental changes in those factors governing
passive or carrier-mediated transport across the
absorptive barrier. Systemic bioavailability becomes
an important consideration when compounds are
absorbed from extravascular administration sites.
The absorptive characteristics of the compound and
the possible influence of first-pass effects may limit
the systemic bioavailability of the compound. This
may lead to lower plasma concentrations of the
compound and reduced exposures.
2.1. Gastrointestinal absorption
Table 1 summarizes the age-dependent anatomical
and physiological factors that may influence the rate
and / or extent of gastrointestinal absorption. Developmental changes in one or any combination of
these factors may explain the differences in absorp-
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Table 1
Age-dependent factors affecting gastrointestinal absorption and the resultant pharmacokinetic outcome relative to adult levels a
Newborn
(full-term)
Neonate
(1 day–1 month)
Infant
(1 month–2 years)
Physiological factor
Gastric pH
Gastric emptying time
Intestinal surface area
Intestinal transit time
Pancreatic and biliary function
Bacterial flora
Enzyme / transporter activity
1–3
Reduced (variable)
Reduced b
Reduced
Very immature
Very immature
Very immature
.5
Reduced (variable)
Reduced b
Reduced
Immature
Immature
Immature
|Adult
Increased
|Adult
Increased
|Adult
Immature
Approaching adult
Pharmacokinetic outcome
Rate and extent of absorption
Gastrointestinal first-pass effects
Variable
Very reduced
Variable
Reduced
$Adult
Approaching adult
a
b
Adapted from Besunder et al. [7].
From Ref. [8].
tive characteristics between newborns and young
infants relative to the adult. The developmental
pattern of these processes may be highly variable and
environmental factors (i.e., diet, concomitant drugs)
[5], genetic factors and underlying pathophysiology
(electrolyte abnormalities, endocrinopathies, CNS
disorders, gastrointestinal disease) [6] may potentially influence their postnatal developmental pattern.
In general, newborns exhibit a slower rate of
absorption [6]. Age-dependent differences in the
extent of absorption (bioavailability) remain largely
unknown [8]. However, bioavailability (the fraction
of parent compound reaching the systemic circulation) will likely change with postnatal age due to
maturation of the processes governing absorption.
2.1.1. Gastrointestinal secretions
Gastrointestinal pH affects the absorption of weakly acidic and basic organic compounds. At birth,
newborns have an alkaline gastric pH (pH 6–8)
[9,10]. Gastric acid production increases over the
next 24–48 h to achieve adult pH levels (pH 1–3)
[11–13]. Following this initial burst of hydrochloric
acid secretion, gastric acid production declines and
gastric acidity remains relatively low in the first
months of life [11,14]. Postnatal increases in gastric
acid production generally correlate with postnatal
age [15] and, on a per kg basis, adult levels are
approached by 2 years of age [16].
The pharmacokinetic consequences of high gastric
pH in the newborn and young infant may involve
enhanced bioavailability of weakly basic compounds,
but reduced bioavailabilities of weakly acidic compounds. This may explain the increased bioavailability of ampicillin and penicillin G (basic drugs)
[17–19] and decreased bioavailability of phenobarbital (acidic drug) [19,20] observed in young infants.
Certain compounds require pancreatic exocrine
and biliary function for adequate absorption. Newborns have immature pancreatic and biliary function
at birth [21]. The levels of most pancreatic enzymes
are significantly reduced [22], and bile formation,
bile acid pool size (50% adult values), bile acid
synthesis and metabolism, and bile acid intestinal
absorption are all reduced in the newborn [23–25].
Pancreatic and biliary function rapidly develop in the
postnatal period [22,26]. A deficiency of bile salts
and pancreatic enzymes may result in a reduction in
the bioavailability of those drugs that require
solubilization or intraluminal hydrolysis (i.e., prodrug esters) for adequate absorption.
2.1.2. Gastrointestinal motility
Gastrointestinal motility may affect the rate and /
or extent of drug absorption. In general, newborns
exhibit delayed gastric emptying rates and prolonged
intestinal transit times relative to the adult [27,28].
The full-term newborn infant demonstrates qualitatively similar gastrointestinal motility patterns with
the adult, but premature infants exhibit disorganized
J. Alcorn, P. J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667–686
and inefficient motility patterns [29,30]. In general,
feeding triggers the postnatal development of gastrointestinal motility [5]. Reduced gastrointestinal
motility may have variable and unpredictable effects
on drug bioavailability in newborns and young
infants. In general terms, delayed gastric emptying
may reduce the rate of drug absorption since the
small intestinal mucosa acts as the principal absorptive site for most drugs. Alternatively, slower intestinal transit times may improve drug bioavailability
due to longer retention times in the small intestine.
The exact effect of developmental maturation of
gastrointestinal motility on drug bioavailability depends upon the physico-chemical properties of the
drug and its interaction with the anatomical and
physiological factors of the gastrointestinal tract.
2.1.3. Gastrointestinal metabolism and transport
Bacterial flora, principally concentrated in the
ileum and colon [31], may influence the extent of
drug absorption due to its influence on gastrointestinal motility and ability to metabolize compounds
[32]. At birth, infant gastrointestinal flora is very
immature and little information is available on the
effect of postnatal maturation of bacterial flora on
bioavailability [32,33]. In general, the bacterial flora
of the infant gastrointestinal tract approaches adult
populations by 4 years of age [34].
The proximal small intestine acts as the principal
absorptive site and site for significant first-pass
effects for many orally administered compounds. In
the adult, the small intestinal mucosa functionally
expresses a limited number of phase I and phase II
enzymes and their expression has led to significant
inter- and intra-individual variability in oral bioavailability [35]. Cytochrome P450 (CYP) 3A4 is the
predominant CYP enzyme expressed in enterocytes
[36,37], and CYP2C has the second highest expression levels [37]. Very low activity levels for CYP1A1
[38] and CYP2D6 [35,39] were detected in intestinal
microsomes. The maturation of CYP enzymes in the
intestinal mucosa remains largely uninvestigated.
One study reported significantly lower CYP3A4
activity levels in intestinal microsomes from infants
aged 0–3 months and a developmental increase in
activity with age [40]. As well, CYP3A7, the fetal
hepatic form of CYP3A, appears to lack expression
in extrahepatic tissues [41].
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The developmental maturation of gastrointestinal
Phase II conjugation enzymes [42–47] remains
unknown. However, b-glucuronidase activity of the
infant small intestine has been reported to exceed
adult activities by as much as 7-fold [48]. This
enhanced b-glucuronidase activity may enable reabsorption of glucuronide drug conjugates. For drugs
that undergo enterohepatic recirculation (i.e.,
chloramphenicol, indomethacin) b-glucuronidase activity enhances their bioavailability.
The adult intestinal tract functionally expresses
various members of the ATP-binding cassette and
solute carrier transporter families [49,50]. These
transporters may have an important impact on drug
absorption and bioavailability in the small intestine
[51], but their exact role remains largely unknown.
The literature provides evidence of postnatal maturation of transport protein activities in other organ
systems [52–58] suggesting gastrointestinal transporter function may also undergo a postnatal maturation.
2.2. Gastrointestinal first-pass effects
The gastrointestinal tract may play an important
role in the first pass metabolism of an orally administered compound [51]. Consequently, developmental
maturation of gastrointestinal metabolic and transport
function may have significant consequences in gastrointestinal first-pass effects and oral bioavailability.
In adults, some drugs undergo extensive metabolism
in the gastrointestinal tract with a concomitant
marked reduction in their oral bioavailability [59–
61]. Immature gastrointestinal metabolic reactions
may result in improved oral bioavailability as gastrointestinal first-pass metabolism has less influence
on the extent of absorption of such drugs. Conversely, some drugs are dependent upon carrier-mediated
uptake systems in the intestinal mucosa for their
efficient absorption [62]. Immature development of
transport function may lead to significantly reduced
oral bioavailability.
Some transporter proteins expressed in the intestinal mucosa promote the active extrusion of drug
from the enterocyte back into the lumen of the
gastrointestinal tract after its absorption (i.e., MDR1)
[63,64]. These transporter proteins compete with
absorption processes and may decrease the rate of
absorption and, potentially, the oral bioavailability.
J. Alcorn, P. J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667–686
672
The interplay between CYP3A4 and the active efflux
transporter, MDR1, illustrates this concept [63,64].
Again, immature development of these active efflux
processes may result in enhanced oral bioavailability.
The exact effect of postnatal maturation on oral
bioavailability will depend upon the interaction of
the principal factors influencing bioavailability
(physico-chemical properties of the compound,
physiology and anatomy of the gastrointestinal tract,
metabolic enzymes, transport processes) [51] and the
degree of their postnatal maturation.
3. Distribution
Postnatal changes in body composition, extent of
binding to plasma proteins and tissue components,
and hemodynamic factors (cardiac output, tissue
perfusion and membrane permeability) may alter
distribution characteristics in the developing infant.
The apparent volume of distribution (Vd ) provides a
useful marker to assess age-related changes in drug
distribution.
3.1. Body composition and tissue perfusion
Body composition may significantly affect drug
Vd . Changes in body composition correlate with both
gestational and postnatal age. Table 2 illustrates total
body water, total protein and total fat content in the
newborn, during infancy and in the adult stages.
Total body water decreases significantly in the early
postnatal period [65], while total body fat increases
progressively in the first months of life [66].
Age-related changes in total body water are primarily attributed to decreases in the relative percentage of extracellular water [65,67]. Extensive
tissue binding or partitioning into fat contribute to
large Vd values. Polar compounds generally exhibit Vd
equivalent to total body water or blood volumes.
Hence, age-related changes in fat, muscle and total
body water composition may produce significant
quantitative changes in Vd and plasma concentrations.
In newborns, the high relative proportion of total
body water and low proportion of fat results in a
general increase in Vd for water-soluble compounds
and a lower Vd for fat-soluble drugs relative to adults.
Key pharmacokinetic parameters (i.e., clearance
and volume of distribution) are often ‘normalized’
according to total body weight or body surface area.
Therefore, it is critical to understand the developmental changes in these body indices with postnatal
age, which is depicted in Fig. 1. While both total
body weight and surface area rise steadily during the
first year of life, a considerable change in their ratio
occurs during the initial 3 months of life.
Developmental changes in Vd may also relate to
postnatal enhancements in cardiac output, organ
blood flows and tissue perfusion, changes in membrane permeabilities [70–72] and maturation of
carrier-mediated transport systems [55–58,73–75],
and changes in tissue binding affinities or capacities
since newborns and young infants have significantly
Table 2
Developmental changes in body composition (reported as a
percentage of total body mass)a
Age
Body
mass
(kg)
Water
Protein
Fat
Newborn: full-term
4 months
12 months
Adult
3.5
7.0
10.5
70
74
61.5
60.5
55–60 b
11
11.5
15
–
14
27
24.5
–
a
b
Adapted from Geigy Scientific Tables [66].
Obesity decreases the percentage of total body water.
Fig. 1. Age-related changes in body weight, body surface area
(BSA) and the ratio of body weight to BSA. Data from the Center
for National Health Statistics at the CDC [68] and Taketomo et al.
[69].
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greater liver, kidney and brain masses relative to
total body mass [66,67,76].
3.2. Plasma protein binding
Postnatal development of plasma protein binding
may affect both the distribution and elimination of
compounds in the newborn and young infant. In
general, newborns and young infants exhibit larger
unbound fractions of a compound relative to the
adult. This may result in enhanced distribution into
tissues and a larger Vd . Age-related differences in
plasma protein binding affinity, plasma protein concentrations and availability of competing endogenous
compounds largely explain the differences in the
extent of binding.
Compounds bind principally to albumin and
alpha 1 -acid glycoprotein. Albumin is the major
plasma protein [77], and concentrations of alpha 1 acid glycoprotein, an acute phase reactant protein
[78], fluctuate significantly in response to various
diseases, trauma or chemical insult [79,80]. In general, the newborn may exhibit lower binding affinities
of compounds (i.e., penicillin, phenobarbital, phenytoin and theophylline) [81] to albumin and a 1 -acid
glycoprotein [82–84]. High unbound fractions may
lead to significantly larger Vd values, and enhanced
renal clearance by glomerular filtration and hepatic
clearance of low extraction ratio compounds in the
newborn.
Developmental changes in plasma protein concentrations have the most significant affect on the
extent of plasma protein binding in the young infant.
Total plasma protein levels are lower in the newborn
relative to the adult [85]. Lower plasma protein
levels reduce the plasma protein binding capacity in
the newborn. Fig. 2 illustrates the postnatal increase
in albumin and alpha 1 -acid glycoprotein concentrations relative to adult levels. A strong correlation
exists between the postnatal increase in plasma
albumin concentrations and the fraction bound [86].
This suggests adult binding characteristics (i.e.,
unbound fraction) for a given compound and the
ratio of infant and adult albumin concentrations may
provide an estimate of infant unbound fractions for
that compound [86]. On the other hand, a weak
correlation exists between the postnatal increase in
Fig. 2. General pattern of ontogeny for albumin (ALB) and alpha
1-acid glycoprotein (AAG) in newborns and infants. Data adapted
from [86] and are expressed as fraction of adult serum concentration (mg / dl).
a 1 -acid glycoprotein plasma concentrations and the
fraction bound in the infant relative to the adult [86].
Several endogenous substances (i.e., bilirubin,
fatty acids) may compete for plasma protein binding
sites [82,87–89]. This competition may further reduce the bound fraction of a compound in the
newborn, or cause displacement of the endogenous
molecule from its protein binding sites. For instance
hyperbilirubinemia reduces the binding of the acidic
drugs ampicillin, penicillin, phenobarbital and
phenytoin [81,90]. Conversely, displacement of bilirubin by drugs (i.e., sulfonamides) may enhance the
risk for bilirubin encephalopathy [7]. Hepatic and
renal disease, hypoproteinemia due to malnutrition,
cystic fibrosis, burns, malignant neoplasms, surgery,
trauma and acidosis may further decrease plasma
protein drug binding due to decreased protein synthesis or competition for binding.
4. Elimination
Systemic clearance provides a measure of the
efficiency of elimination and is often the most
important pharmacokinetic determinant of plasma
concentrations and resultant response (see Eq. (1)).
In general, hepatic and / or renal elimination pathways effect the removal of most compounds from the
body. These pathways are generally underdeveloped
and inefficient in the newborn. The various pathways
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of elimination mature at different rates and patterns
of development and maturation to adult levels (adjusted for body weight differences) is generally
achieved after the first year of postnatal life. Recent
in vitro and in vivo probe substrate data have
provided important information on the maturation
characteristics of hepatic and renal elimination mechanisms (reviewed in Alcorn and McNamara, 2002)
[91]. This data provides the basis for the proceeding
discussion. Additionally, for more in depth discussion of the maturation of systemic clearance mechanisms the reader is referred to excellent reviews by
Hakkola et al. [92], Ring et al. [93], Gow et al. [94],
McCarver and Hines [95], Hines and McCarver [96],
de Wildt et al. [97], and Hayton [98].
4.1. Hepatic clearance
Hepatic blood flow, plasma protein binding and
intrinsic clearance (defined as the maximal enzymatic or transport capacity of the liver) constitute
the physiological determinants of hepatic clearance
[99,100]. Each of these determinants undergoes
significant postnatal changes, and their maturation
results in an enhanced capacity for hepatic elimination of compounds with advancing postnatal age.
4.1.1. Intrinsic clearance
Intrinsic clearance processes principally govern
the capacity of newborns to eliminate drug by the
liver. Although hepatocellular transport and biliary
excretion processes contribute to intrinsic clearance
and are deficient at birth [74,101,102], hepatic
biotransformation processes have the greatest impact
on hepatic drug elimination in the developing infant.
Phase I and Phase II reactions principally mediate
the metabolism of compounds in the developing
infant. Often a compound undergoes sequential
metabolism with Phase I metabolic reactions preceding Phase II metabolism [103].
Of the phase I reactions, cytochrome P450 (CYP)
enzymes have the most important role in the elimination of most compounds. The postnatal maturation of
other Phase I enzymes, such as the alcohol and
aldehyde dehydrogenases, esterases and the flavincontaining monooxygenases, are reviewed in Hines
and McCarver, 2002 [96]. Important phase II reactions include glucuronidation, sulfation, gluta-
thione conjugation, and acetylation. Since most
compounds are eliminated by more than one metabolic pathway, postnatal changes in the efficiency of
Phase I and Phase II reactions, differences in their
rate and pattern of development, and changes in the
hepatocellular distribution and expression of Phase I
and Phase II enzymes [104] may have a significant
impact on the qualitative and quantitative characteristics of hepatic elimination in the newborn and
developing infant. To predict the exact nature of
these consequences requires an understanding of the
postnatal maturation of the individual hepatic metabolic pathways that mediate drug and toxicant removal from the body.
4.1.1.1. Cytochrome P450 enzyme-mediated metabolism
The CYP enzymes represent a superfamily of
heme-containing enzymes [105]. CYP1A2, CYP2A6,
CYP2B6, CYP2C’s, CYP2D6, CYP2E1, and
CYP3A4 / 7 comprise the principal CYP enzymes
important in drug and toxicant metabolism [106–
108]. The rate and pattern of postnatal CYP enzyme
development may have a significant impact on
therapeutic efficacy and toxicant susceptibility in the
newborn and developing infant. Interindividual differences in their developmental patterns, genetic
polymorphisms, and their induction / inhibition potential further complicate the role of CYP enzyme
maturation on pharmacokinetics in the newborn and
young infant.
The postnatal maturation of CYP enzymes is
evidenced in numerous literature reports of shortening half-lives and enhanced hepatic elimination of
drugs in developing infants [109,110]. These studies
suggest hepatic metabolic pathways undergo rapid
postnatal development. Recently, in vitro studies
have examined the maturation of individual CYP
enzymes in age-dependent fetal and infant hepatic
microsomes [111–115]. These studies corroborate
the findings of the in vivo studies and have further
elucidated the maturation characteristics of individual CYP enzymes. As well, these studies have shown
the CYP enzymes mature at characteristic rates and
patterns of development and may be grouped according to their general developmental pattern of activity
[116]. Fig. 3 highlights the general pattern of CYP
enzyme development as a fraction of adult levels
J. Alcorn, P. J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667–686
Fig. 3. General pattern of postnatal development of the hepatic
clearance pathways in newborns and infants. Data adapted from
[91] and are expressed as fraction of adult clearance values
(ml / min / kg). The general classification was adapted from Cresteil, 1998 [116]. (CYP, cytochrome P450 enzyme; UGT, Uridine
59-diphosphate-glucronosyltransferase; ST, Sulfotransferase; NAT,
N-acetyltransferase; GST, Glutathione-S-transferase).
based upon enzyme activity values (normalized to
mg microsomal protein) from age-specific fetal,
neonatal and infant hepatic microsomes [116].
In vitro assessments have revealed significantly
lower levels of CYP enzyme protein and activity in
the fetus (total CYP enzyme protein levels are onethird adult levels) [107,117,118]. These data are
consistent with literature reports demonstrating the
ability of the fetal liver to metabolize a variety of
drug substrates [116,119]. For most CYP enzymes,
though, fetal activity levels are only a small fraction
of adult activity levels, and parturition triggers their
postnatal development [92–94,116]. Consequently,
the newborn has a limited capacity for hepatic
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biotransformation and, in general, CYP enzyme-mediated metabolism improves with postnatal age and
generally approaches adult levels only after the first
year of life [117,120]. Table 3 summarizes the
maturation of individual CYP enzyme activity levels
based upon in vitro determinations of CYP enzyme
activity in fetal, infant and adult age group hepatic
microsomes [111–115].
4.1.1.1.1. Maturation
of
individual
CYP
enzymes Fetal hepatic microsomes exhibit negligible
CYP1A2 enzyme activity [107,121,122]. CYP1A2
enzyme activity remains very low after birth and
significant in vitro activity is detected only by 1–3
months of age [112]. By the first year of life
CYP1A2 enzyme activity levels are only 50% adult
values and mature to adult activity levels sometime
after a year of age [112,120]. This pattern of
development explains the long half-life and low
systemic clearance values of theophylline in the
newborn [123]. Immature CYP1A2 enzyme development prevents the biotransformation of theophylline
resulting in prolonged half-lives in the newborn and
infant. Significant increases in theophylline systemic
clearance values are observed only after 1–3 months
of age [123,124]. This pattern of theophylline clearance with advancing postnatal age reflects the postnatal development of in vitro CYP1A2 enzyme
activity in the infant.
Fetal livers fail to express CYP2A6 and CYP2B6
enzyme activity [107,122]. Otherwise, the postnatal
development of CYP2A6 and CYP2B6 remains
largely unknown. Both CYP enzymes likely achieve
adult capacities only after the first year of life [120].
Fetal and newborn (,1 week of age) livers
demonstrate very limited CYP2C enzyme activity
Table 3
In vitro cytochrome P450 (CYP) enzyme activity in age-specific fetal and infant hepatic microsomes as a fraction of adult activity (nmol
min 21 mg microsomal protein 21 )
CYP
enzyme
Fraction of adult activity
Fetus
,24 h
1–7 d
8–28 d
1–3 m
3–12 m
1–15 y
1A2
2C
2D6
2E1
3A4
3A7
0.05
–
0.04
–
0.03
5
0.12
0.02
0.04
0.21
0.08
9.5
0.10
0.03
0.09
0.31
0.13
13
0.20
0.42
0.24
0.36
0.29
6
0.39
–
–
0.46
0.34
3
0.46
0.29
–
0.39
0.43
2
1.10
–
–
0.80
1.08
–
Adapted from Refs. [111–115].
676
J. Alcorn, P. J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667–686
[118,125]. Within the first month of postnatal life,
CYP2C enzyme activity surges to 50% adult levels
[114,117]. After this surge of activity, CYP2C
enzyme activity levels decline slightly for the first
year of life and adult levels are reached sometime
after 1 year of age [114,117,120]. As a substrate of
the CYP2C enzyme subfamily, diazepam metabolite
urinary levels are consistent with the in vitro pattern
of CYP2C enzyme development. Newborns exhibit
very low urinary diazepam metabolite levels [114].
However, diazepam urinary metabolite levels increase significantly in infants greater than 1-weekold [114]. Thereafter, metabolite levels remain relatively stable in children up to 5 years of age [114].
Fetal livers may express very low levels of
CYP2D6 enzyme activity [107,113]. A dramatic
increase in CYP2D6 activity occurs in the immediate
postpartum period. By the first month of life,
CYP2D6 enzyme activity levels reach |30% adult
levels [113], and CYP2D6 maturation may be completed by 1 year of age [120]. In vivo assessment of
the hepatic clearance of CYP2D6 substrates is
lacking in the newborn and young infant.
Fetal hepatic microsomes may express low levels
of CYP2E1 enzyme activity [126]. Parturition triggers a dramatic increase in CYP2E1 enzyme activity
within the first 24 h of life [115]. CYP2E1 enzyme
activity levels achieve 50% adult levels by 1–3
months of age and development is essentially complete after 1 year of age [115].
CYP3A subfamily is the most abundantly expressed CYP enzyme in the liver [106,127].
CYP3A4 enzyme is the principal enzyme of the adult
liver [106], while fetal livers predominantly express
CYP3A7 enzyme [111,128,129]. Although CYP3A4
and CYP3A7 enzymes exhibit 95% similarity in their
nucleotide sequences [130], important differences in
substrate specificities exist between these two
CYP3A enzymes [107,111,131]. Few studies have
examined the substrate profile of CYP3A7 enzyme.
The ability of fetal livers to metabolize a wide
variety of substrates [119] suggests CYP3A7 enzyme
also may metabolize a wide range of substrates and
demonstrate some substrate overlap with CYP3A4
enzyme.
Total CYP3A enzyme protein levels remain relatively constant throughout development [111]. Fetal
livers demonstrate high levels of CYP3A7 enzyme
activity and express limited CYP3A4 enzyme activity (|10% adult levels) [111,122]. CYP3A7 enzyme
activity levels peak 1 week after parturition, then
declines significantly during the first year of life
[111,120]. Adult livers may express only 10% fetal
levels [111,132]. During the postnatal period, activity levels of CYP3A4 enzyme increase concomitantly
with the decreases in CYP3A7 enzyme activity
[111]. CYP3A4 enzyme activity reaches 30–40%
adult levels by 1 month of age and adult levels by 1
year [111,120]. The pharmacokinetic consequences
of this postnatal developmental switch from
CYP3A7 to CYP3A4 remain largely unknown since
the substrate profile of CYP3A7 enzyme has received limited investigation. However, some studies
suggest newborns and adults will exhibit significant
differences in their capacity to eliminate known
CYP3A4 enzyme substrates. For example, premature
and full-term newborns eliminate the CYP3A4 enzyme substrate, midazolam, with poor efficiency
[133]. A 5-fold increase in the elimination efficiency
of midazolam occurs by 3 months of age [134].
These data suggest midazolam is not an efficient
CYP3A7 enzyme substrate.
4.1.1.2. Phase II metabolism
Phase II or conjugation reactions contribute significantly to the elimination of a wide variety of
exogenous and endogenous compounds. Glucuronidation, sulfation, acetylation, glutathione conjugation, comprise the most important Phase II pathways in drug and toxicant metabolism. In general,
changes in the expression patterns of the different
Phase II enzymes or changes in their catalytic
efficiency may occur with development. Such
changes may have important consequences on the
elimination of compounds in the newborn and young
infant. In general, inefficient conjugation capacity of
the newborn will result in a significant reduction in
the ability of the newborn to eliminate both exogenous and endogenous compounds. Table 4 and Fig. 3
summarize the known maturation patterns of important Phase II enzymes. For a more in depth
discussion of the development of Phase II metabolic
pathways, the reader is referred to the review by
McCarver and Hines [95].
4.1.1.2.1. Maturation of individual conjugation
reactions The uridine 59-diphosphate-glucrono-
J. Alcorn, P. J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667–686
Table 4
Maturation patterns of phase II enzymes
Phase II enzyme
Maturation pattern
UGT
Fetal livers exhibit limited enzyme activity;
activity |25% adult levels at 3 months;
maturation is isoforms specific; adult
activity levels achieved by 6–30 months.
ST
Fetal livers exhibit significant activity;
maturation is isoform specific.
GST
Fetal livers exhibit significant activity;
maturation is isoform specific; total
activity remains stable throughout infancy.
NAT
Fetal livers exhibit low activity; low
activity at birth through the first months of
life; adult levels achieved after 1 year of age.
UGT, Uridine 59-diphosphate-glucronosyltransferase; ST,
Sulfotransferase; NAT, N-acetyltransferase; GST, Glutathione-Stransferase.
syltransferases (UGT) enzymes consist of two
families, UGT1 and UGT2, containing more than 18
different enzymes [97,135]. More than one UGT
enzyme may participate in the metabolism of a single
substrate [136,137], and the maturation of UGT
enzyme capacity is isoform specific [97,138]. Consequently, the developmental rate and pattern of individual UGT enzymes may explain the tremendous
variability reported in the glucuronidation capacity of
newborns and infants. In their review on the developmental maturation of glucuronidation capacity
in the infant, de Wildt et al. suggest the clinical
relevance of the development of individual UGT
enzyme capacity in infants remains unclear [97].
As a whole, newborns and young infants demonstrate inefficient glucuronidation capacity relative to
the adult [139–141]. Fetal livers exhibit limited UGT
enzyme activity [142,143]. Fetal hepatic microsomes
(15–27 weeks gestation) catalyzed morphine glucuronidation at only 10–20% the efficiency of adult
hepatic microsomes [144,145]. Parturition triggers an
increase in UGT enzyme activity and UGT enzyme
activity achieves |25% adult levels by 3 months of
age [143]. The in vivo postnatal elimination pattern
of the UGT enzyme substrate, morphine, is consistent with the in vitro studies. Premature and fullterm infants have a markedly reduced and variable
677
capacity to eliminate morphine, and adult levels were
achieved by 6–30 months of age [146,147].
Sulfotransferases (ST) consist of a number of
individual enzymes and have substrate specificities
that demonstrate significant overlap with the UGT
enzymes [148]. Although changes in activity of the
individual ST enzymes with development occur, the
data on their development is limited and confusing.
In general, fetal, newborn and infant livers express
significant ST activity, and sulfate conjugation is a
relatively efficient pathway at birth [149–151]. Consequently, the newborn and young infant may eliminate ST enzyme substrates very efficiently. For
instance, the ST and UGT enzyme substrate ritodrine, a b 2 -adrenoceptor agonist, underwent extensive
sulfate conjugation in infants [149]. The study
demonstrated no age-related differences in the overall systemic clearance of ritodrine, only quantitative
differences in metabolite levels (glucuronide conjugates and sulphate conjugates) between infants and
adults [149].
Glutathione-S-transferases (GST) represent a
superfamily of dimeric enzymes responsible for the
detoxification of a number of potentially toxic drug
or drug metabolites [152]. Five different subunit
classes ( m, a, u, p and z ) of GST enzymes have
been classified [152,153]. As with the ST enzymes,
the GST enzymes demonstrate age-related expression
of individual enzymes in the liver [154–156]. For
example, preterm newborn livers exhibited 60%
greater activity towards chloramphenicol than fetal
livers, but showed similar activity levels towards
chlorodinitrobenzene [157]. However, the literature
remains sparse and presents conflicting information
with respect to individual enzyme development
[156,157]. In general, though, GST activity is relatively well-developed in the newborn and infant, and
total GST activity may remain relatively stable
throughout development [158]. The clinical significance of the quantitative and qualitative differences
in the developmental expression of individual GST
enzymes remains unknown, but may have important
implications in toxicant susceptibility.
N-acetyltransferases (NAT) consist of two enzymes, NAT1 and NAT2, and NAT2 demonstrates
polymorphic activity [159–161]. Very limited data
exists on the developmental expression of NAT1 and
NAT2 enzyme activity. Fetal livers express activity
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J. Alcorn, P. J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667–686
towards several NAT enzyme substrates, but at much
lower levels than the adult [47,162]. Consequently,
the newborn exhibits a limited capacity to acetylate
substrates. The acetylation status of the infant may
reflect adult levels only well past the first year of life
[163–165].
4.1.1.3. Consequences of variability in the postnatal
maturation of phase I and phase II reactions
Many compounds undergo multiple routes of
metabolism. Quantitative and qualitative differences
in the developmental expression profiles of metabolic
pathways of the liver may modify the rate and
pattern with which newborns and infants eliminate
compounds throughout development. These interindividual differences may lead to altered metabolite
profiles as the relative contribution of the different
routes of metabolism may vary with infant age.
Differences in metabolite profiles become significant
when a particular metabolite has pharmacological or
toxicological activity. Consequently, the rate, pattern
and extent of metabolic pathway maturation are
important considerations in the pharmacokinetic
consequences of postnatal maturation of hepatic
clearance pathways. Interindividual differences in the
rates and patterns of individual elimination pathway
maturation may largely explain the tremendous
interindividual variation observed in the capacity of
newborns and infants to eliminate drugs. Superimposed upon the interindividual variability in metabolic enzyme maturation is the influence of metabolic
enzyme induction and / or inhibition. In utero and / or
postnatal exposure to certain exogenous or endogenous compounds may cause rapid enzyme induction
or inhibition in the fetus, newborn and infant [166].
This will further exacerbate the variable rate and
pattern of enzyme maturation. For example, newborns treated concomitantly with barbiturates, a
CYP2C inducer [114], exhibited a marked reduction
in diazepam (a CYP2C substrate) half-lives (t 1 / 2 5
1861 h) as compared with newborns treated with
diazepam alone (t 1 / 2 53162 h) [114,167]. Furthermore genetic polymorphisms in CYP2D6, CYP2C9,
CYP2C19, CYP2E1, UGT and NAT [168] may
further enhance the interindividual variability in drug
elimination characteristics observed in infants. Polymorphisms in drug metabolism and the potential for
enzyme induction and / or inhibition complicate any
assessment of elimination capacity in the newborn
and young infant.
4.1.2. Hepatic first-pass effects
For many drugs subject to first-pass effects,
hepatic metabolism results in a significant reduction
in the oral bioavailability of a compound. Postnatal
maturation of metabolic enzyme pathways and hepatocellular transport systems may result in significant
differences in the oral bioavailability of compounds
in the newborn and young infant relative to the adult.
For all orally administered compounds, plasma protein binding and intrinsic clearance determine the
extent of parent drug bioavailability [99]. Newborns
generally exhibit lower plasma protein binding capacities. Higher unbound fractions of an absorbed
compound may theoretically enhance oral clearance
and result in lower oral bioavailability of the compound. For most drugs, intrinsic clearance has the
most important effect on bioavailability. At birth,
immature Phase I and Phase II metabolic enzyme
pathways and hepatocellular transport processes may
significantly reduce the extent of first-pass hepatic
metabolism of an absorbed compound. Inefficient
hepatic metabolism in the newborn may cause
enhanced oral bioavailabilities relative to the adult.
Maturation of the hepatic metabolic pathways will
result in age-related reductions in oral bioavailability. As with hepatic clearance, interindividual
differences in the rate and pattern of metabolic
enzyme pathway maturation may cause significant
interindividual variation in oral bioavailability during
postnatal development. Hence, postnatal maturation
of hepatic metabolism may greatly influence therapeutic efficacy and toxicant susceptibility because
hepatic metabolism may determine the both the oral
bioavailability of a compound and the efficiency with
which the newborn or young infant may remove that
compound from the body.
4.2. Renal clearance
Renal clearance mechanisms include glomerular
filtration (GFR), tubular secretion and tubular reabsorption. At birth, these renal clearance mechanisms are incompletely developed and renal elimination capacity of the newborn is significantly compromised [169–171]. During late gestation and early
J. Alcorn, P. J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667–686
postnatal development profound anatomical and
functional changes in the kidney greatly enhance
renal elimination efficiency in the first few months of
life [172,173]. Renal functions demonstrate a rapid
maturation and generally reach adult levels before 1
year of age [174–176]. Maturation of glomerular
filtration and renal tubular functions proceed at
different rates and patterns resulting in marked
interindividual variability in renal elimination efficiency.
The anatomical and functional development of the
kidney continues throughout gestation into the early
postnatal period. Nephrons increase in number until
nephrogenesis is completed at 36 weeks of gestation
[172,173,177,178]. Prior to 36 weeks gestation, then,
changes in renal function principally correlate with
increases in the number of nephrons [179–181].
Incomplete nephrogenesis in the pre-term newborn
will compromise glomerular and tubular function
[182]. Functional maturation and growth processes
explain the changes in renal elimination capacity in
the full-term infant [98,172]. In general, postnatal
functional maturation of the kidney is associated
with enhancements in renal blood flow, improvements in glomerular filtration efficiency and the
growth and maturation of renal tubules and tubular
processes [98].
4.2.1. Glomerular filtration
During the fetal stages, GFR capacity is significantly reduced [172]. Parturition triggers enhancements in both cardiac output and renal blood flow
and a dramatic decrease in renal vascular resistance
and a redistribution of blood flow within the kidney
[172,183–185]. These hemodynamic changes cause a
rapid increase in GFR during the early postnatal
period [4,171,186–190]. At birth, GFR, normalized
to body surface area, in the full-term infant is 10–15
ml / min / m 2 [169,171], but increases to 20–30 ml /
min / m 2 within the first 2 weeks of life [171,191]. By
6 months of age, infant GFR, normalized to body
surface area has approached adult levels (73 ml /
min / m 2 ) [192]. Rapid improvements in GFR result
in rapid enhancements in the renal clearance of
compounds principally eliminated by GFR.
Postnatal improvements in GFR correlate with
gestational age rather than postnatal age [4,193–
195]. Premature infants exhibit lower GFR values on
679
average and a slower pattern of GFR development
during the first 1–2 weeks postpartum as compared
with the full-term infant [4,183,196]. With completion of nephrogenesis and maturation of glomerular
function, enhancements in GFR in the preterm infant
will proceed at the same rate as full-term infants
[183]. However, even by 5 weeks of age the absolute
value for GFR remains lower in preterm infants
[183]. This functional delay in GFR in preterm
infants is an important consideration in the estimation of an infant’s capacity for renal elimination.
Interestingly, Fig. 4 illustrates infant GFR, on an
ml / min / kg basis, is roughly comparable to the adult
[185]. This implies adult renal clearance values
normalized to a body weight may reasonably predict
infant renal clearances on a body weight basis.
4.2.2. Renal tubular function
At birth, the renal tubules exhibit significant
anatomic and functional immaturity [197]. Incomplete anatomical development of renal tubules compromises both passive reabsorption [188,198] and
active secretion and reabsorption processes [199–
201]. In addition to limited tubular size and functional maturity, poor peritubular blood flow, reduced
urine concentrating ability, and lower urinary pH
values further compromise renal tubule function in
the newborn [202]. In general, renal tubular growth
processes, maturation of renal tubular transport systems, and redistribution of blood flow to the secretory areas of the kidney account for the enhancements
Fig. 4. General pattern of postnatal development of the renal
clearance pathways in newborns and infants. Developmental
changes in glomerular filtration rate (GFR), renal tubular secretion
(TS) and renal blood flow (Q R ). Data adapted from [98] and are
expressed as fraction of adult clearance values (ml / min / kg).
680
J. Alcorn, P. J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667–686
in renal tubular function during postnatal development [171,187,203]. As the infant develops, maturation of renal tubular function generally exhibits a
more protracted time course than GFR. This
produces a functional glomerulotubular imbalance
until renal tubule maturation is completed by 1 year
of age [204,205].
Numerous protein carrier systems mediate active
renal excretion and reabsorption. Their postnatal
development at the renal tubular epithelium and their
impact on renal elimination efficiency in the newborn and infant remains largely unknown. Functionally, the kidney exhibits a reduced capacity to
excrete weak organic acids like penicillins, sulfonamides, and cephalosporins [200,201]. Newborn
kidneys excrete p-aminohippurate (PAH), a substrate
for the organic anion transporters, at 20–30% adult
levels [187], and adult excretion levels are approached by 7–8 months of age [176]. Premature
and full-term infants excrete furosemide, a PAH
transport pathway substrate, slowly with plasma halflives of 19.9 and 7.7 h, respectively, as compared
with 0.5 h in the adult [206,207]. In utero or infant
exposure to certain agents may induce or inhibit
renal tubular transport functions [174]. Transport
induction or inhibition may compound the variability
observed in renal clearance values in newborns and
young infants. The low urinary pH values relative to
the adult may influence the reabsorption of weak
organic acids and bases, and differences in renal
drug elimination may reflect a discrepancy in urinary
pH values [166].
The anatomical and functional immaturity of the
newborn kidney leads to reduced renal clearances of
compounds during the early postnatal period. Differences in the rate of development of glomerular
filtration and tubular function (i.e., the
glomerulotubular imbalance) and the potential for the
induction or inhibition of renal glomerular and tubule
transport function [208] may have variable and
complex effects on the renal elimination.
5. Conclusions
Postnatal maturation of pharmacokinetic processes
has significant implications with respect to systemic
exposure levels and the safety and / or efficacy of a
compound in the newborn and young infant. Func-
tional immaturity of absorption, distribution, metabolism and / or excretion processes contribute to the
disparate responses observed between newborns,
infants and adults. Premature infants present a further complication as the anatomical and functional
immaturity of the organs and other biochemical and
physiological processes involved in drug pharmacokinetics is further exacerbated. An assessment
of the therapeutic efficacy or toxicant susceptibility
of a newborn to an exposure will require a careful
consideration of the developmental aspects of pharmacokinetic processes. In general, the combined
effects of age-related changes in each pharmacokinetic process on plasma levels of a compound
are poorly understood. Clinical studies encompassing
newborns and infants within narrow postnatal age
groups are needed to enhance our understanding of
the pharmacokinetic and clinical consequences of
postnatal maturation of absorption, distribution, metabolism and excretion processes. Such information
will help to establish more effective guidelines to
predict an exposure outcome in a newborn or young
infant and to ensure safe exposures to therapeutic or
inadvertent compounds.
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