เภสัชจลนศาสตร์
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Transcript เภสัชจลนศาสตร์
Pharmacokinetics
ผศ.มนุพศั โลหิตนาวี
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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.
Passive
Diffusion across the cell
membrane
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