Transcript metabolism - Farmasi Unand

METABOLISM
Dr. Muslim Suardi, MSi., Apt.
Faculty of Pharmacy
University of Andalas
2008
ELIMINATION
“The irreversible removal of drug from the
body by all routes of elimination”
• Metabolism
• Excretion
METABOLISM
Biotransformation
The process by which the drug is chemically
converted in the body to a metabolite
Enzymatic
Non Enzymatic (ester hydrolysis)
Place of Metabolism
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Mainly: Liver
Kidneys
Lung
Small Intestine
Skin
GI mucosal cells
Microbiological flora in the distal portion of
the ileum & large intestine
Metabolism in The Liver
Clearance
“The process of drug elimination from the
body or from the single organ without
identifying the individual processes
involved”
The volume of fluid cleared of drug from
the body per unit of time (mL/min)
BIOTRANSFORMATION
REACTIONS
Active drug to inactive metabolite
Amphetamine
Phenylacetone
Active drug to active metabolite
Codeine
Morphine
Inactive drug to active metabolite
Hetacillin
Ampicllin
Active drug to reactive intermediate
PCT
Reactive metabolite
REACTIONS
• Phase I
More polar metabolites
A-synthetic reactions
• Phase II
Conjugation
Synthetic reactions
Much more polar metabolites
Phase I
• Occurs first
• Introduce or expose a functional group on
drug mol
• Oxygen into phenyl group of
phenylbutazone by aromatic hydroxylation
to form oxyphenbutazone
• Codeine is demethylated to form morphine
• Hydrolysis of ester Aspirin to form Salicylic
Acid
Phase I
• Oxidation
Aromatic hydroxylation
Side chain hydroxylation
N-, O-, and S-dealkylation
Deamination
Sulfooxidation, N-oxidation
N-hydroxylation
• Reduction
Azoreduction
Nitroreduction
Alcohol dehydrogenase
• Hydrolysis
Ester hydrolysis
Amide hydrolysis
Phase II
• Salicylic Acid with glycine to form
salicyluric acid
• Salicylic Acid with glucoronic acid to form
salicylglucoronide
• Conjugating reagents
• Derived from biochemical compounds
involved carbohydrate, fat, & protein
metabolism
Phase II
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Glucuronidation
Sulfation
Amino acid conj
Acetylation
Methylation
Glutathione conj
by
by
by
by
by
by
Glucuronic acid
Sulfate
Glycine
Acetyl CoA
CH3
glutathione
Hepatic Elimination
K = km + ke
The rate constant of elimination (K) =
first-order rate constant for metabolism (km)
+ the first-order rate constant for excretion
(ke)
Clinical Focus
• The overall el half life (t1/2) of a drug is 2
hr (K=0.3465/hr, km=0.104/hr).
• If the renal excretion pathway becomes
impaired as in the case of certain kidney
disorders, then less or none drug will be
excreted renally & hepatic metabolism
may become the primary drug elimination
route.
Clinical Focus
K
but ke
thus k
= km + ke,
= 0,
= km.
T1/2
= 0.693/k.
t1/2
= 0.693/0.104
= 6.7 hr
Variation of Biotransformation
Enzymes in Humans
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Genetics Factors
Environmental Factors
Drug Interactions
Physiologic Conditions
Drug Dosage Regimen
Genetics Factors
• Genetic different within population
• Racial differences among different
populations
Environmental Factors
Enzyme induction
Enzyme inhibition
Drug Interactions
Enzyme induction
Enzyme inhibition
Physiologic Conditions
Age
Gender
Diet/Nutrition
Pathophysiology
Drug Dosage Regimen
Route of drug administration
Dose dependence (nonlinear)
pharmacokinetics.
Pharmacogenetics
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“Genetic differences in drug elimination “
INH
N-acetylation
Rapid & slow acetylation
Slow acetylation
neurotoxicity
The differences is referred to as genetic
polymorphism.
Genetic Polymorphism
• Procainamide
acetylated
• Hydralazin
acetylated
• Glucose-6-phosphate-dehydrogenase
deficiency, approximately 10% of black
Americans
• Phenytoin, Efficient & Poor Metabolizer
• Propranolol, difference among Chinese
population
DI Involving Drug Metabolism
The enzymes involved in the
metabolism of drugs may be altered by:
• Diet
• Co-administration of other drugs &
chemicals
Enzyme Induction
A drug or chemical-stimulated increase in
enzyme activity usually due to an increase
in the amount of enzyme present
• Eg.:
Phenobarbital
Carbamazepine
Rifampicin
Benzopyren (Smoking)
Chlordane (Insecticide)
Enzyme Inhibition
• May be due to substrate competition or
due to direct inhibition of drug
metabolizing enzyme, particularly one of
several of the cytochrome P-450 enzymes.
• Eg.: Fluoxetine decrease the Cl of IMI due
to its inhibitory effect of hydroxylation.
Inhibition
Inhibitors
Example
PCT
EtOH
Cimetidine
Erythromycin
Result
Increased
hepatotoxicity
Warfarin
Prolongation of
prothrombin
time
Carbamazepine
Decreased
Carbamazepine
Cl
Induction
Inducers of
drug
metabolism
Carbamazepine
Example
Result
PCT
Increased PCT
metabolism
Rifampin
Methadone
Increased
methadone
metabolism
First Pass Metabolism
First Pass Effect
• Routes of administration may affects the
metabolic rate
• A drug given parenterally, transdermally,
or by inhalation may distribute within the
body prior to metabolism by the liver.
First Pass Effect
• In contrast, drugs given orally are normally
absorbed in the duodenal segment of the
small intestine and transported via the
mesenteric vessels to the hepatic portal
vein & then to the liver prior to the
systemic circulation.
First Pass Effect
• Drugs that are highly metabolized by the
liver or by the intestinal mucosal cells
demonstrate poor systemic availability
when given orally.
• This rapid metabolism of an orally
administered drug prior to reaching the
general circulation is termed FPE or presystemic elimination.