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Pharmacokinetics
ผศ.มนุพศั โลหิตนาวี
[email protected]
[email protected]
Outline
Introduction
Physicochemical properties
Absorption, Bioavialability,
routes
of admistration
Distribution
Biotransformation (Metabolism)
Excretion
Clinical pharmacokinetics
Components of
pharmacokinetics
 Input,
dosing by using routes of
administration
 Pharmacokinetic processes (figure 1,
drawing)
– Absorption
– Distribution
– Biotransformation (Metabolism)
– Excretion
Cell membrane
barrier
of drug permeation
(drawing), with semipermeable
property
factors affecting drug across cell
membrane
– cell membrane properties
– physicochemical properties of drugs
Cell membrane
physicochemical
properties
of drugs
–size and shape
–solubility
–degree of ionization
–lipid solubility
Cell membrane
Characteristics
of Cell membrane
– Lipid bilayer: mobile horizontally,
flexible, high electrical resistance
and impermeable to high polar
compounds
– protein molecules function as
receptors or ion channels or sites
of drug actions.
Diffusion across the cell
membrane
 Passive
transport (drawing)
– higher conc to lower conc area
– energy independent
– at steady state both sides have equal
conc.(non electrolye cpds)
– electrolyte: conc. of each side depends
on pH (fig 2)
– weak acid and weak base
Diffusion across the cell
membrane
 Carrier-mediated
membrane
transport (drawing)
– lower conc to higher concentration
area (agianst concentration gradient)
– structure specific
– rapid rate of diffusion
– Active and Facillitated transport
Diffusion across the cell
membrane
 Active
transport
– energy dependent
– structure specific, inhibited by
structure-related cpds, saturable
 Facillitated
transport
– energy independent
– structure specific, inhibited by
structure-related cpds, saturable
 Drawing
 almost
Saturable process
all protein-mediated process
in our body can occur this process
saturation not only transport system
but also others such as enzymatic
reaction, drug-ligand binding and so
on.
 because functional protein molecules
are limited.
 Parameters
Drug absorption
in drug absorption
– Rate constant of drug absorption (Ka)
– Bioavialability (F)
 Anatomical
aspects affecting absorption
parameters (Drawing)
– GI tract (metabolzing organ and barrier of drug
movement)
– Liver (portal and hepatic vien, excretion via
biliary excretion)
– cumulative degradation so called “First pass
effect”
Drug absorption
 Factors
affecting drug absorption
(Drawing)
– Physicochemical properties of drugs
– pH at site of absorption
– Concentration at the site of
administration
– Anatomical and physiological factors
Blood
flow
Surface area
Routes of administration
Enteral
and parenteral routes
Pros and cons between
Enteral and parenteral
Enteral administration
 Pros
– most economical,
– most convenient
Cons
–high polar cpds could not be absorbed
–GI irritating agents
–enzymatic degradaion or pH effect
–Food or drug interaction (concomitant used)
–cooperation of the patients is needed
–first pass effect due to GI mucosa
Parenteral administration
Pros
– Rapidly attained
concentration
– Predictable conc by the
calculable dose
– Urgent situation
Cons
–Aseptic technic must be employed
–Pain
–limited self adminstration
–More expensive

Enteral administration
Common
use of enteral
administration
–Oral administration
–Sublingual administration
–Rectal administration
Enteral administration
 Concentrion-time
course of oral
administration (Drawing)
 Rapid increase in plasma conc until
reaching highest conc and subsequent
decrease in plasma conc
 Drawing (concept of MTC and MEC)
– Absorption phase
– Elimination phase
Enteral administration
Prompt
release: the most
common dosage form
Special preparation:
Enteric-coat, SR
SR, Controlled release:
Purposes and limitation
Enteral administration
 Sublingual
administration
– Buccal absorption
– Superior vana cava directly: no first pass
effect
– Nitroglycerin (NTG): highly extracted by the
liver, high lipid solubility and high potency
(little amount of absorbed molecules be able
to show its pharmacological effects and relieve
chest pain).
Enteral administration
 Rectal
adminstration
– unconscious patients, pediatric patients
– 50% pass through the liver and 50%
bypass to the inferior vena cava
– lower first pass effect than oral
ingestion
– inconsistency of absorption pattern
– incomplete absorption
– Irritating cpds
Parenteral administration
 Common
use of parenteral administration
– Intravenous
– Subcutaneous
– Intramuscular
 Simple
diffusion
 Rate depends on surface of the capillary,
solubility in interstitial fluid
 High MW: Lymphatic pathway
Parenteral administration
 Intravenous
– precise dose and dosing interval
– No absorption (F=1), all molecules reach blood
circulation
– Pros: Calculable, promptly reach desired conc.,
Irritating cpds have less effects than other
routes
– Cons: unretreatable, toxic conc, lipid solvent
cannot be given by this route (hemolysis), closely
monitored
Parenteral administration
Subcutaneous
– suitable for non-irritating
cpds
– Rate is usually slow and
constant causing prolonged
pharmacological actions.
Parenteral administration
Intramuscular
– more rapid than subcutaneous
– rate depends on blood supply to
the site of injection
– rate can be increased by
increasing blood flow (example)
Pulmonary absorption
 gaseous
or volatile substances and aerosol
can reach the absorptive site of the lung.
 Highly available area of absorption
 Pros: rapid, no first pass effect, directly
reach desired site of action (asthma,
COPD)
 Cons: dose adjustment, complicated
method of admin, irritating cpds.
Bioequivalence
 Pharmaceutical
equivalence (drawing)
 Bioequivalence: PharEqui+ rate+
bioavialable drugs
 Factors:
– Physical property of the active
ingredient: crystal form, particle size
– Additive in theformulation: disintegrants
– Procedure in drug production: force
An example of a generic product that could
pass a bioequivalence test: Simvastatin
(Parent form, n=18)
Plasma concentration (ng/ml)
8.00
6.00
A
4.00
B
2.00
0.00
0
4
8
12
Time (hr)
16
20
24
An example of a generic product that could
pass a bioequivalence test: Ondansetron (n=14)
Serum ondansetron concentration (ng/mL)
60
A
B
40
20
0
0
6
12
Time (hr)
18
24
An example of a generic product that
could pass a bioequivalence test:
Clarithromycin (n=24)
Plasma clarithromycin concentration
(ng/mL)
2500
2000
Klacid (A)
Claron (B)
1500
1000
500
0
0
4
8
12
Time (h)
16
20
24
Distribution
 Drawing
 distribution
site: well-perfused organs,
poor-perfused organs, plasma proteins
 Well-perfused: heart, liver, kidney, brain
 Poor-perfused: muscle, visceral organs,
skin, fat
Distribution
 Plasma
proteins
– Albumin: Weak acids
– alpha-acid glycoprotein: Weak bases
 Effects
of plasma protein binding
– Free fraction: active, excreted, metabolized
– the more binding, the less active drug
– the more binding, the less excreted and
metabolized:
“longer half-life”
Distribution
 Effects
tissues
of well distribution into the
– deep tissue as a drug reservoir
– sustain released drug from the
reservoir and redistributed to the site
of its action
– prolong pharmacologic actions
Distribution
CNS and CSF
 Blood-Brain
Barrier (BBB)
– unique anatomical pattern of the vessels
supplying the brain
– only highly lipid soluble compounds can
move across to the brain
– infection of the meninges or brain:
higher permeability of penicillins to the
brain.
Distribution
Placental transfer
 Simple
diffusion
 Lipid soluble drug, non-ionized
species
 first 3 mo. of pregnancy is very
critical: “Organogensis”
Biotransformation
 Why
biotranformed? (Figure 5)
– Normally, drugs have high lipid solubility
therefore they will be reabsorbed when the
filtrate reaching renal tubule by using tubular
reabsorption process of the kidney.
– Biotransformation changes the parent drug to
metabolites which always have less lipid
solubility (more hydrophilicity) property
therefore they could be excreted from the
body
Biotransformation
Biotransformation
– to more polar cpds
– to less active cpds
– could be more potent (M-6-G)
or more toxic (methanol to
formaldehyde)
Biotransformation
Phase
I and II
Biotransformation
– Phase I : Functionization,
Functional group
– Phase II: Biosynthetic,
Molecule
Biotransformation
Phase
I Reactions (Table 2)
– Oxidation
– Reduction
– Hydrolysis
Biotransformation
Phase
II Reactions (Table 3)
– Glucuronidation
– Acetylation
– Gluthathione conjugation
– Sulfate conjugation
– Methylation
Biotransformation
 Metabolite
from conjugation reaction
– Possibly excreted into bile acid to GI
– Normal flora could metabolize the
conjugate to the parent form and
subsequently reabsorbed into the blood
circulation. This pheonomenon is socalled “Enterohepatic circulation”
which can prolong drug half-life.
Biotransformation
Site
of biotransformation
– Mostly taken place in the liver
– Other drug metabolizing organs:
kidney, GI, skin, lung
– Hepatocyte (Drawing)
Biotransformation
The Liver: Site of biotransformation:
– mostly enzymatic reaction by using the
endoplasmic reticulum-dwelling enzymes.(Phase
I), Cytosolic enzymes are mostly involved in
the phase II Rxm.
– Method of study phase I Rxm
Breaking
liver cells
Centrifugation very rapidly
microsomes and microsomal enzymes
Biotransformation
 Cytochrome
(figure 6)
P450 monooxygenase system
– microsomal enzymes
– Oxidation reaction using reducing agent
(NADPH), O2
– System requirement
 Flavoprotein
(NADPH-cytochrome P450 reductase,
FMN+FAD) fuctions as an electron donor to
cytochrome c.
 Cytochrome P450 (CYP450)
Biotransformation
 Steps
in oxidative reactions (figure 6)
– Step 1:Parent + CYP450
– Step 2:Complex accepts electron from
the oxidized flavoprotein
– Step 3:Donored electron and oxygen
forming a complex
– Step 4: H2O and Metabolite formation
Biotransformation
 CYP450
is a superfamily enzyme, many
forms of them have been discovered (12
families).
 Important CYP450 families in drug
metabolism (Fig. 7)
– CYP1 (1A2)
– CYP2 (2E1, 2C, 2D6)
– CYP3
Biotransformation
 Factors
affecting biotransformation
– concurrent use of drugs: Induction and
inhibition
– genetic polymorphism
– pollutant exposure from environment or
industry
– pathological status
– age
Biotransformation
 Enzyme
induction
– Drugs, industrial or environmental
pollutants
– increase metabolic rate of certain drugs
leading to faster elimination of that
drugs.
– “autoinduction”
– Table 4
Biotransformation
Enzyme
induction
– important inducers:
antiepileptic
agents,
glucocorticoids for CYP3A4
isoniazid, acetone, chronic use of
alcohol for CYP2E1
Biotransformation
Enzyme inhibition: (drawing)
– Competitive binding and reversible:
Cimetidine, ketoconazole, macrolide
metabolites
– Suicidal inactivators: Secobarbital,
norethindrone, ethinyl estradiol
– Clinical significance: erythormycin and
terfenadine or astemizole causing
cardiac arrhythmia.
 Genetic
Biotransformation
polymorphism
– Gene directs cellular functions through its
products, protein.
– Almost all enzymes are proteins so they have
been directed by gene as well.
– Drug-metabolizing enzymes:
 Isoniazid:
causing more neuropathy in caucaasians
leading to identification of the first characterized
pharmacogenetics.
 due
to the rate of N-acetylation: Slow and fast
acetylators
Biotransformation
Pathologic
conditions
– Hepatitis
– Cirrhosis due to chronic alcohol intake
– Hypertensive pts recieving propranolol which
lowers blood supply to the liver may lead to
less biotransformation of the high extraction
drugs such as lidocaine, propranolol, verapamil,
amitryptyline
Excretion
 Parent
and metabolite
 Hydrophilic compounds can be easily
excreted.
 Routes of drug excretion
–
–
–
–
Kidney
Biliary excretion
Milk
Pulmonary
 Renal
Excretion
excretion: Normal physiology
– Glomerular filtration: Free fraction, filtration
rate
– Active tubular secretion: Energy dependent,
carrier-mediated, saturable
 Acids:
penicillins and glucuronide conjugate (uric
excretion)
 Bases:choline, histamine and endogenous bases
– Passive tubular reabsorption
non-ionized species back diffuse into blood
circulation
Excretion
 Clinical
application of urine pH modification
Drug toxicity
– Weak base: Acidic urine pH enhances drug
excretion by increasing numbers of inoized
species by using ammonium chloride.
– Weak cid: Basic urine pH enhances drug
excretion by increasing numbers of inoized
species by using sodium bicarbonate.
Excretion
Cationic,
anionic and
glucuronide conjugates can be
excreted into bile acid and show
enterohepatic cycle.
Clinical pharmacokinetics
Assumption:
correlation
between blood concentration
and effects
MEC and MTC (figure 8)
Therapeutic range
Clinical pharmacokinetics
Order
of reaction
– zero order pharmacokinetics
(Drawing): ethanol, high dose
phenytoin and aspirin
– first order pharmacokinetics: most
drugs show first order
pharmacokinetic fashion.
Clinical pharmacokinetics
 Data:
relationship between
concentration and time (Drawing)
 Compartmental model to explain above
relationship (fig. 9)
 Dosing and route of administration:
IV bolus, IV infusion and oral
ingestion
Clinical pharmacokinetics
 Using
first order:
– IV bolus: concentration-time curve
profile (fig 10)
– explain equation number 1
– which leads to these pharmacokinetic
parameters: clearance, volume of
distribution, half-life, Css, onset,
duration, F
Clinical pharmacokinetics
Clearance
Vd
Half-life and Elimination constant
Onset
Duration
Steady state concentration
Absolute bioavialability