Download General Pharmacokinetics

GENERAL
PHARMACOKINETICS
Assoc. Prof. I. Lambev
Medical University of Sofia
www.medpharm-sofia.eu
(Abstract)
Pharmacokinetics
– how does the
human body
act on the drugs?
Pharmacokinetics is the quantitative study of
drug movement in, through and out of the body.
Intensity of effect is related to the concentration
of the drug at the site of action, which depends
on its pharmacokinetic properties.
Pharmacokinetic properties of the drug
determine the route(s) of administration, dose,
latency of onset, time of peak action, duration
of action and frequency of drug administration.




All pharmacokinetics processes involve transport
of the drug across biological lipid membrane.
Passive diffusion Filtration
through lipid
Carrier transport
Passive transport
- Passive diffusion
- Filtration
Specialized transport
- Carrier transport
Active transport
Facilitated diffusion
- Pinocytosis, etc.
Convection
Passive (simple) diffusion
The lipid soluble unionized drug diffuse across
the lipid biomembrane in the direction of their
concentration gradient. It does not need energy.
Most drugs are week electrolytes. Their ionization
is pH dependent. The ionization of a week acid (AH)
is given by the equation of Henderson–Hasselbalch:
[AH]
pKa = pH + log10 -----[A ]
pKa is the negative logarithm of acidic dissociation
constant of the week electrolyte. If the concentration
of unionized drug [AH] is equal to concentration of
ionized drug [A-], then
[AH]
--------- = 1
[A-]
since log 1 is 0, under this condition pH = pKa
In this case the molecules of drugs are 50% ionized.
For a week base:
pKb = pH +
[BH+]
log10 -----[B]
Filtration
Filtration is passage of a drug through aqueous pores
in the membrane through paracelullar spaces.
The moving force is hydrostatic or osmotic pressure.
Lipid insoluble drugs cross the biomembrane by
filtration only if their molecular size is smaller than
the diameter of the enlarged aqueous pores.
The filtration has an importance mainly at the level
of renal glomerulus, where the size of capillaries have
large pores (40 Å) and most drugs (even albumin)
can filtrate. The brain capillary pores have small size.
Carrier transport –
by combination with a carrier molecule which acts as
a ferry-boat across the lipid region of the membrane.
Carrier transport is saturable and competitively
inhibited by analogues which utilize the same carrier.
a) Active transport is a movement against the concentration gradient. It needs energy and is inhibited
by metabolic poisons.
Levodopa and methyldopa are actively absorbed
from the gut by aromatic amino acid transport.
b) Facilitated diffusion. This proceeds more rapidly
than passive (simple) diffusion and translocates
even nondiffusible substrates, but along their
concentration gradient, therefore, does not
need energy. Example: Facilitated transport of glucose.
Pinocytosis involves the invagination of a part
of the cell membrane and trapping within the cell
of a small vesicle containing extracellular constituents. The vesicle contents can than be released
within the cell, or extruded from the other side of
the cell. Pinocytosis is important for the transport
of some macromolecules (e.g. insulin through BBB).
I. ABSORPTION
It is the passage of drug from the site
of administration into the circulation.
Aqueous solubility. Drugs given in solid form must
dissolve in the aqueous biophase before they are
absorbed. For poorly water soluble drugs (aspirin,
griseofulvin) the rate of dissolution governs the rate
of absorption. If a drug is given as water solution,
it is absorbed faster than the same given in solid
form or as a oily solution.
Concentration. Passive transport depends on the
concentration gradient. A drug given as concentrated
solution is absorbed faster than dilute solution.
Area of absorbing surface. If the area is larger,
the absorption is faster.
Vascularity of absorbing surface. Blood circulation removes the drug from the site of absorption
and maintains concentration gradient across the
membrane. Increased blood flow hastens
drug absorption.
Route of administration affects drug
absorption, because each route has its
own peculiarities.
Oral application. Unionized lipid soluble drugs (e.g.
ethanol) are readily absorbed from GIT. Acid drugs (aspirin, barbiturates, etc.) are predominantly unionized in the
acid gastric juice and are absorbed from the stomach. Acid
drugs absorption from the stomach is slower, because the
mucosa is thick, covered with mucus and the surface is small.
Basic drugs (e.g. atropine, morphine, etc.) are largely ionized and are absorbed only from the duodenum.
Presence of food dilutes the drug and retards absorption.
Certain drugs form poorly absorbed complexes with food
constituents, e.g. tetracyclines with calcium present in milk.
Food delays gastric emptying.Most drugs are absorbed
better if taken on an empty stomach. Highly ionized drugs,
e.g. amikacin, gentamicin, neostigmine, are poorly
absorbed when given orally.
Certain drugs are degraded in the GIT, e.g. penicillin G
by acid, insulin by peptidases, and are ineffective orally.
Enteric coated tablets (having acid resistant coating) and
sustained released preparations can be used to overcome
acid ability, gastric irritancy and brief duration of action.
Intestinal absorption:
2+
- duodenum (B1, Fe )
- ileum (B12, A, D, E, K)
- large intestine
+
+
(water, Na , Cl , K )
Drugs can also alter absorption by gut wall effect:
altering motility (atropine, amitriptyline, pethidine,
methoclopramide) or causing mucosal damage
(neomycin, methotrexate, reserpine, vinblastine).
Alteration of gut flora by antibiotics may disrupt the
enterohepatic recirculation of oral contraceptives
and digoxin.
S.c. and i.m. application
By these routes the drug is deposited in the vicinity of
the capillaries. Lipid soluble drugs pass readily across
the whole surface of the capillary endothelium, but
very large molecules are absorbed through lymphatics.
Many drugs not absorbed orally are absorbed parenterally.
Absorption from s.c. site is slower than that from i.m. site,
but both are generally faster and more predictable than
p.o. absorption. Application of heat and muscular exercise
accelerate drug absorption by increasing blood flow.
Application of vasoconstrictors (e.g. adrenaline) retard
absorption. Many depot preparations (preparations with a
long action), such as benzatine benzylpenicillin and
protamine zinc insulin can be given by these routes.
Topical applications
(skin, cornea, mucous membranes)
Systemic absorption depends on lipid solubility.
Only a few drugs significantly penetrate intact skin.
Nitroglycerine, hyoscine (scopolamine) and estradiol
have been used in this manner. Glucocorticosteroids
(GCS) applied over extensive areas can produce
systemic effects and pituitary-adrenal suppression.
Cornea is permeable to lipid soluble, unionized physostigmine but not to highly ionized neostigmine.
Similarly, the mucous membrane of the mouth,
rectum and vagina absorb lipophilic drugs, e.g.
estrogen cream applied intravaginally has produced
gynecomastia in the male partner.
Bioavailability refers to the rate and extent of
absorption of a drug from dosage form as determined
by its concentration-time curve in blood or by its excretion
in urine. It is a measure of the fraction (F) of administered
dose of a drug that reaches the systemic circulation in the
unchanged form.
Bioavailability of a drug injected i.v. is 100%, but is
frequently lower after oral ingestion, because:
a) The drug may incompetely absorb
b) The absorbed drug may undergo first pass
metabolism in intestinal wall and/or liver, or be
excreted in bile.
Plasma concentration (mcg/ml)
AUC – area under the curve
F – bioavailability
AUC p.o.
F = ------------ x 100%
AUC i.v.
(i.v. application)
(p.o. application)
0
5
Time (h)
10
15
Plasma concentration time curves of the three preparations of a drug
which contain the same amount. Formulation B is more slowly absorbed
than A and may not produce therapeutic effect. Formulation C is absorbed
to a lesser extent (it has lower bioavailability).
II. DISTRIBUTION
In studying the pharmacokinetics biosystems
conditionally divided into separate parts –
compartment (or phases).
They are virtual spaces in which the drug
is evenly distributed. They are distinguished
each other in the volume of distribution
and invasion (penetration) and
evazionnite (release) rate constants.
The distribution of the drugs is a dynamic process,
during which they pass from the central (plasma)
compartment in the tissue to reach steady state
(steady state – ss). It depends on the mode of
administration and the pK of the drug, its ability
for binding to plasma protein, pH of the medium,
organ perfusion.
The number of compartments is determined for
each drug according to the experimental data
measured concentrations at different moments
in the blood, urine and body fluids.
Two-compartment pharmacokinetic model
Body fluid compartments
The total body water as a percentage of body
mass varies from 50% to 70%, being rather
less in women than in man.
Body water is distributed
into the following main compartments:
1. plasma (5% of body mass)
2. intestinal fluid (16%)
3. intracellular fluid (35%)
4. transcellular fluid (2%)
5. fat (20%)
Apparent volume of distribution (Vd)
It is accept that the body behaves as a single
homogeneous compartment with volume (Vd)
in which the drug gets immediately distributed:
Dose administered
Vd = ----------------------------Plasma concentration
Drugs extensively bound to plasma proteins are largely
restricted to the vascular compartment and have low Vd
(e.g. warfarin – 99% bound and its Vd is 0,1 L/kg).
Drugs sequestrated in other tissues may have Vd much
more than the total body water or even body mass, e.g.
digoxin (6 L/kg) and propranolol (3 to 4 L/kg) because
most of the drug is present in other tissues, and the
plasma concentration is low.
Therefore, in case of poisoning, drugs with large
Vd are not easily removed by haemodialysis.
Redistribution. Highly lipid soluble drugs given i.v.
or by inhalation get distributed to organs with high
blood flow (brain, heart, kidney, liver). Later they get
distributed to less vascular tissues (muscles and fat)
and the drug-plasma concentrations falls.
The greater lipid solubility of the drug hastens its
redistribution. Anaesthetic action of thiopentone
(thiopental) is terminated in few minutes due to
redistribution. However, when the same drug is given
repeatedly or continuously over long periods the low
perfusion high capacity sites get progressively filled
up and the drug becomes longer acting.
Thiopental
(thiopentone)
-redistribution in
muscle
and fat
(long postnarcotic
sleep)
Blood brain barrier (BBB): includes the capillary endothelial cells (which have tight junctions and lack large
intracellular pores) and an investment of glial tissue,
over the capillaries. A similar barrier is loctated in
the choroid plexus.
BBB is lipid and limits the entry of non-lipid soluble
drugs (amikacin, gentamicin, neostigmine etc.).
Only lipid soluble unionized drugs penetrate and
have action on the CNS.
Efflux carriers like P-gp (glycoprotein) present in brain
capillary endothelial cells (also in intestinal mucosal,
renal tubular, hepatic canicular, placental, and testicular
cells) extrude drugs that enter the brain by other processes.
Inflammation of the meninges of the brain increases
permeability of the BBB.
Dopamine (DA) does not enter the brain, but its precursor
levodopa does. This is used later in parkinsonism.
GIT
L-DOPA
Blood and
peripheral
tissues
Brain
1–3%
(Levodopa)
70%
DDC
DDC
МАО
COMT
27–29%
DDC – DOPA-decarboxilase; COMT – catechol-О-methyltransferase
Placental barrier. Placental membranes are lipid
and allow free passage of lipophilic drug, while restricting
hydrophilic drugs. The placental P-gp also serves to
limit foetal exposure to maternally administered drugs.
However restricted amounts of nonlipid soluble drugs,
when present in high concentration or for long periods
in maternal circulation, gain access to the foetus. Thus, it
is an incomplete barrier and many drugs, taken by the
mother, can affect the foetus or the newborn.
Penicillins, azithromycin, and erythromycin do not affect
the foetus and can be used during the pregnancy.
Plasma protein binding (PPB). Most drugs possess
physicochemical affinity for plasma proteins. Acidic
drugs bind to plasma albumin and basic drugs
to α1-glycoprotein. Extent of binding depends on the individual compound. Increasing the concentration of a drug
can progressively saturate the binding sites. The clinical
significant implications of PPB are:
a) Highly PPB drugs are largely restricted to the vascular
compartment and tend to have lower Vd.
b) The PPB fraction is not available for action.
c) There is an equilibration between the PPB fraction of
the drug and the free molecules of the drug.
d) The drugs with high physicochemical affinity for
plasma proteins (e.g. aspirin, sulfonamides,
chloramphenicol) can replace the other drugs
(e.g. acenocoumarol, warfarin) or endogenous
compounds (bilirubin) with lower affinity.
e) High degree of protein binding makes the drug longacting, because bound fraction is not available for
metabolism, unless it is actively excreted by the liver
or kidney tubules.
f) Generally expressed plasma concentrations of the drug
refer to bound as well as free drug.
g) In hypoalbuminemia, binding may be reduced and high
concentration of free drug may be attained (e.g. phenytoin).
Tissue storage. Drugs may also accumulate in specific
organs or get bound to specific tissue constituents, e.g.:
Heart and skeletal muscles – digoxin (to muscle proteins)
Liver – chloroquine, tetracyclines, digoxin
Kidney – digoxin, chloroquine
Thyroid gland – iodine
Brain – chlorpromazine, isoniazid, acetazolamide
Retina – chloroquine (to nucleoproteins)
Iris – ephedrine, atropine (to melanin)
Bones and teeth – tetracyclines, heavy metals
(to mucopolysaccharide of connective tissue)
Adipose tissues – thiopental, ether, minocycline, DDT
III. METABOLISM (BIOTRANSFORMATION)
Metabolism includes chemical alteration of the drugs in
the body. Most hydrophilic drugs (amikacin, gentamycin,
neostigmine, mannitol) are not biotransformated and are
excreted unchanged. The mechanism to metabolize drugs
is developed to protect the body from toxins. The primary
site for drug metabolism is the liver, other sites are the
kidney, intestine, lungs, and plasma.
Metabolism of drugs may lead to the following:
a) Inactivation. Most drugs and their active metabolites
are converted to less active or inactive metabolites, e.g.
phenobarbital, morphine, propranolol, etc.
b) Active metabolite from an active drug. Many drugs
are converted to one or more active metabolites (e.g.
diazepam, amitriptyline).
c) Activation of inactive drug. Few drugs (so called
prodrugs) are inactive as such. They need conversion
in the body to one or more active metabolites (e.g.
levodopa, benfothiamine, enalapril, perindopril).
The prodrug may offer advantages: their active forms
may be more stable; they can have better bioavailability
(e.g. benfothiamine), or other desirable
pharmacokinetic properties or less
side effects and toxicity.
Biotransformation reactions can be classified into two
phases: I (no synthetic) and II (synthetic, conjugation).
Phase I (no synthetic reactions)
a) Oxidation is the most important drug metabolizing
reaction. Various oxidation reactions are hydroxylation;
oxygenation at C-, N- or S-atoms; N or 0-dealkylation,
oxidative deamination, etc. Oxidative reactions are
mostly carried out by a group of monooxygenases in
the liver, which in the final step involve cytochrome P450
reductase and O2. There are more than 200 cytochrome
P450 isoenzymes, differing in their affinity for various
substances (drugs). They are grouped into > 20 families.
CYP 3A4/5 carry out biotransformation of the largest number (≈ 50%) of
drugs. In addition to the liver, these isoforms
are expressed in the intestine (responsible for first pass
metabolism at this site) and the kidney too. Inhibition of
CYP 3A4 by erythromycin, clarithromycin, ketoconzole,
itraconazole, verapamil, diltiazem, and a constituent of
grape fruit juice are responsible for unwanted interaction
with terfenadine. Rifampicin, phenytoin, carbmazepine,
phenobarbital are inducers of the CYP 3A4.
Substrates:
Cumarins
CYP2B6
CYP2A6
<5%
Mephenytoin
Omeprazole
CYP2C19
<5%
Tolbutamide
Warfarin
Phenytoin
CYP2C8/9/18
~20%
Midazolam
Nifedipine
Erythromycin
Cyclosporine
CYP3A4/5
(30–50%)
Caffeine
Theophylline
Tacrine
CYP1A2
~15%
Chlorzoxazone
CYP2E1
~10%
Dextrometorphan
Debrisoquine
CYP2D6
<5%
CYP1A1
Inhibitors:
Methoxsalen Fluconazole Sulphaphenazole
Ketoconazole
Gestodene
Furafylline
Fluvoxamine
Tetrahydro- Quinidine
furane
Inducers:
Phenobarbital
Phenobarbital Phenobarbital
Rifampicin
Rifampicin
Phenobarbital
Rifampicin
Dexamethasone
Carbamazepine
Omeprazole
Nicotine
Ethanol
Isoniazid
Barbiturates, phenothiazines, paracetamol, streroids,
phenytoin, benzodiazepines, theophyllin and many other
drugs are oxydaized by CYP450. Some other drugs
(adrenaline, mercaptopurine) and ethanol are oxidized
by mitochondrial or cytoplasmic enzymes.
b) Reduction. This reaction is conversed
of oxidation and involves CYP450 enzymes
working in the opposite direction.
Drugs, primarily reduced, are
chloramphenicol, halothane.
c) Hydrolysis. This is cleavage of a drug molecule by
taking up a molecule of water.
Ester + H20
Esterase
Acid + Alcohol
Similarly amides and polypeptides are hydrolyzed
by amidase and peptidases. Hydrolysis occurs in the liver,
intestines, plasma, and other tissues. Examples are
choline esters, procaine, lidocaine, pethidine, oxytocin.
d) Cyclization is formation of a ring structure from a
straight chain compound, e.g. proguanil.
e) Decyclization is opening up of a ring structure of
the cyclic molecule, e.g. phenytoin, barbiturates.
Phase II – synthetic (conjugation) reactions
These involve conjugation of the drug or its phase I metabolite with an endogenous substrate to form a polar highly
ionized organic acid, which is easily excreted in urine or
bile. Conjugation reactions have high energy requirements.
(1) Glucoronide conjugation is the most important synthetic reaction. Compounds with a hydroxyl or carboxylic
acid group are easily conjugated with glucuronic acid,
which is derived from glucose, e.g. chloramphenicol,
aspirin, morphine, metronidazole, GCS, bilirubin, thyroxine.
Drug glucuronides, excreted in bile, can be hydrolyzed
in the gut by bacteria, producing beta-glucuronidase.
The liberated drug is reabsorbed and undergoes the same
fate. This enterohepatic recirculation of some drugs (e.g.
chloramphenicol, phenolphthalein, oral contraceptives)
prolongs their action.
(2) Acetylation. Compounds having amino or hydrazine
residues are conjugated with the help of acetyl CoA, e.g.
sulfonamides, isoniazid. Multiple genes control the acetyl
transferases and rate of acetylation shows genetic
polymorphism (slow and fast acetylators).
(3) Sulfate conjugation. The phenolic compounds and
steroids are sulfated by sulfokinases, e.g.
chloramphenicol, adrenal, and sex steroids.
The two phases of drug metabolism
Synthetic (conjugation) reactions:
(4) Methylation. The amines and phenols can be
methylated. Methionine and cysteine act as methyl donors.
Examples: adrenaline, histamine, nicotinic acid.
(5) Ribonucleoside/nucleotide synthesis is important
for the activation of many purine and pyrimidine antimetabolites used in cancer chemotherapy, e.g. Xeloda®.
(6) Only a few drugs are metabolized by enzymes of
intermediary metabolism. Examples:
•alcohol by dehydrogenases
•allopurinol by xanthine oxidase
•succinylcholine and procaine by plasma cholinesterase
•adrenaline by monoamine oxidase (MAO)
FIRST PASS (PRESYSTEMIC) METABOLISM
This refers to metabolism of a drug during its passage
from the site of absorption into systemic circulation. All
orally administered drugs are exposed to drug metabolism in the intestinal wall and liver in different extent.
•High first pass metabolism: propranolol, verapamil,
pethidine, salbutamol, nitroglycerine, morphine, lidocaine.
•Oral dose of these drugs is higher than sublingual or
parenteral dose.
•There is individual variation in the oral dose due to
differences in the extent of first pass metabolism.
•Oral bioavailability is increased in patients with severe
liver disease.
IV. EXCRETION
Excretion is the passage out of
systematically absorbed drugs.
Drugs and their metabolites
are excreted in:
urine (through the kidney)
•bile and faeces
•exhaled air
•saliva and sweat
•milk
•skin
The kidney is responsible for excreting all
water soluble substances.
Glomerular filtration. Glomerular capillaries have large
pores. All nonprotein bound drugs (lipid soluble or insoluble)
presented to the glomerulus are filtrated. Glomerular filtration
of drugs depends on their plasma protein binding and renal
blood flow. Glomerular filtration rate (g.f.r.) declines
progressively after the age of 50 and is low in renal failure.
Tubular reabsorption. Lipid soluble drugs filtrated at the
glomerulus back diffuse in the tubules because 99% of
glomerular filtrate is reabsorbed, but nonlipid soluble
and highly ionized drugs are unable to do so.
Thus, the rate of excretion of such drugs, e.g.
aminoglycoside (amikacin, gentamicin, tobramycin) parallels
g.f.r. Changes in urinary pH affect tubular reabsorption of
partially ionized drugs:
•Weak bases ionize more and are less reabsorbed
in acidic urine.
•Weak acids ionize more and are less reabsorbed
in alkaline urine.
This principle is utilized for facilitating elimination
of drugs in poisoning:
•Urine is acidified in morphine and atropine poisoning.
•Urine is alkalized in barbiturate and salicylate poisoning.
The effect of changes in urinary pH on drug excretion
is greatest for a drug having pK values between 5 to 8,
because only in this case pH dependent passive
reabsorption is significant.
Tubular secretion is the active transfer of organic acid
and bases by two separate nonspecific mechanisms,
which operate in the proximal tubules:
•Organic acid transport for penicillins, probenecid,
salicylates, uric acid, sulfinpyrazones, nitrofurantoin,
methotrexate, drug glucuronides, etc.
•Organic base transport for thiazides, quinine,
procainamide, cimetidine, amiloride, etc.
Many drug interactions occur due to competition
for tubular excretion, e.g.:
•Aspirin blocks uricosuric action of probenecid and sulfinpyrazone and decreases tubular excretion of methotrexate.
•Probenecide decreases the urine concentration of
nitrofurantoin, increases the duration of penicillin action
and impairs excretion of methotrexate.
•Quinidine decreases renal and biliary clearance of digoxin
by inhibiting efflux carrier P-gp.
Tubular transport mechanisms are not well developed
at birth. Duration of action of many drugs (penicillins,
cephalospoins, aspirin, etc.) is longer in neonates.
These systems mature during infancy.
•aminoglycosides
•beta-lactams
•sulfonamides
•quinolones
•nitrofurans
•polymyxins
•macrolides
•lincosamines
•rifampicin
•tetracyclines (p.o.)
•General inhalation
anaesthetics
•Potassium iodide
•Bronchoantiseptic oils
•Alcohol
•sulfonamides
•barbiturates
•reserpine
•alcohol
•Coffeinum
(Caffeine)
Rauwolfia serpentina
(Reserpine: India)
Saliva excretion
•oleandomycin
•spiramycin
•phenytoin
•zalcitabine
•verapamil
Morphine
(10% stomach excretion)
•morphine pKb: 7.9
•stomach pH: 1–2
•plasma pH: 7.36
Poppy
KINETICS OF ELIMINATION
(elimination = metabolism + excretion)
Clearance (Cl) of a drug is the theoretical volume of plasma
from which the drug is completely removed per unit time:
Cl = Rate of elimination/Plasma concentration
Renal (Clr) or creatinine clearance (Clcr):
Curine x Vurine
Clrenal = -------------------Cplasma
First order (exponential) kinetics. For majority of drugs
the processes involved in elimination are not saturated
over the clinically obtained concentrations. These drugs
have first order kinetics. Their rate of elimination is
directly proportional to plasma drug concentration and
their clearance
remains constant.
Semilog plasma
concentration-time
plot of a drug eliminated by first
order kinetics
after i.v. injection.
Zero order (linear) kinetics.
In a few cases where the drugs are inactivated
by metabolic degradation (such as ethanol,
phenytoin, theophylline, salicylates, and warfarin),
the time-course of disappearance of the drug from
the plasma does not follow the exponential or
biexponential pattern, but is initially linear.
These drugs are removed at a constant rate
which is independent of plasma concentration.
This is often called zero order kinetics.
The blood alcohol
concentration
falls linearly and
the rate of fall
does not vary
with dose.
Plasma half live (t1/2) is the time in which the plasma
concentration of a drug declines by one half. Drug with
long t1/2 can accumulate. Plasma t1/2 of some drugs:
Adenosine < 2 sec
Dobutamine – 2 min
Benzylpenicillin – 30 min
Amoxicillin – 1 h
Paracetamol – 2 h
Atenolol – 7 h
Diazepam – 40 h
Ethosuccimide – 54 h
Digitoxin – 168 h
From the peak plasma concentration the drug is virtually eliminated from the plasma in 5 t1/2 periods:
(1)
(2)
(3)
(4)
(5)