BP Metabolism

7/29/2019 BP Metabolism

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METABOLISM

Dr. Muslim Suardi, MSi., Apt.School of Pharmacy

Faculty of Sciences, University of Andalas


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ELIMINATION

The irreversible removal of drug from the

body by all routes of elimination

Metabolism

Excretion


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METABOLISM

Biotransformation

The process by which the drug is chemically

converted in the body to a metabolite

Enzymatic

Non Enzymatic (ester hydrolysis)


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Location of Metabolism

Mainly: Liver

Kidney

Lung

Small Intestine

Skin

GI mucosal cells

Microbiological flora in the distal portion ofthe ileum & large intestine


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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)


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BIOTRANSFORMATION

REACTIONS

Active drug to inactive metabolite

Amphetamine Phenylacetone

Active drug to active metaboliteCodeine Morphine

Inactive drug to active metabolite

Hetacillin Ampicllin

Active drug to reactive intermediatePCT Reactive metabolite


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REACTIONS

Phase I

More polar metabolites

A-synthetic reactions

Phase II

Conjugation

Synthetic reactions

Much more polar metabolites


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Phase I

Occurs first

Introduce or expose a functional group ondrug mol

Oxygen into phenyl group ofphenylbutazone by aromatic hydroxylationto form oxyphenbutazone

Codeine is demethylated to form morphine Hydrolysis of ester Aspirin to form Salicylic

Acid


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Phase I

Oxidation Aromatic hydroxylationSide chain hydroxylation

N-, O-, and S-dealkylation

Deamination

Sulfooxidation, N-oxidationN-hydroxylation

Reduction AzoreductionNitroreduction

Alcohol dehydrogenase

Hydrolysis Ester hydrolysisAmide hydrolysis


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Phase II

Salicylic Acid with glycine to form

salicyluric acid

Salicylic Acid with glucoronic acid to form

salicylglucoronide

Conjugating reagents

Derived from biochemical compoundsinvolved carbohydrate, fat, and protein

metabolism


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Phase II

Glucuronidation by Glucuronic acid

Sulfation by Sulfate

Amino acid conj by Glycine Acetylation by Acetyl CoA

Methylation by CH3

Glutathione conj by glutathione


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Hepatic Elimination

K = km+ ke

The rate constant of elimination (k) = first-

order rate constatn for metabolism (km) +

the first-order rate constant for excretion

(ke)


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Clinical Focus

The overall el half life (t1/2) of a drug is 2hr (k=0.347/hr, km=0.104/hr. If the renalexcretion pathway becomes impaired as in

the case of certain kidney disorders, thenless or none drug will be excreted renally& hepatic metabolism may become theprimary drug el route.

K = km + ke, but ke = 0, thus k = km.

T1/2 = 0.693/k. t1/2 = 0.693/0.104= 6.7 hr


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Variation of Biotransformation

Enzymes in Humans

Genetics Factors

Environmental Factors & Drug Interactions

Physiologic Conditions Drug Dosage Regimen


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Genetics Factors

Genetic different within population

Racial differences among different

populations


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Environmental Factors & Drug

Interactions

Enzyme induction

Enzyme inhibition


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Physiologic Conditions

Age

GenderDiet/Nutrition

Pathophysiology


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Drug Dosage Regimen

Route of drug administration

Dose dependence (nonlinear)pharmacokinetics.


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Pharmacogenetics

Genetic differences in drug elimination

INH

N-acetylation Rapid & slow acetylation

Slow acetylation neurotoxicity

The differences is referred to as geneticpolymorphism.


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Genetic Polymorphism

Procainamide acetylated

Hydralazin acetylated

Glucose-6-phosphate-dehydrogenasedeficiency, which is observed inapproximately 10% of black Americans

Phenytoin, EM & PM (Efficient & Poor

Metabolizer) Propranolol, difference among Chinese

population


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Drug Interactions Involving Drug

Metabolism

The enzymes involved in the metabolism

of drugs may be altered by:

Diet

Co-administration of other drugs &

chemicals


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Enzyme induction

A drug or chemical-stimulated increase in

enzyme activity usually due to an increase

in the amount of enzyme present

Examples: Phenobarbital

Carbamazepine

RifampicinBenzopyren (Smoking)

Chlordane (Insecticide)


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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.

Examples: Fluoxetine decrease the

clearance of IMI due to its inhibitory effect

of hydroxylation.


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Inhibition

Inhibitors Example Result

PCT EtOH Increased

hepatotoxicity

Cimetidine Warfarin Prolongation of

prothrombin

time

Erythromycin Carbamazepine DecreasedCarbamazepine

clearance


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Induction

Inducers of

drug

metabolism

Example Result

Carbamazepine PCT Increased PCTmetabolism

Rifampin Methadone Increased

methadonemetabolism


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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.


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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 portalvein & then to the liver prior to the

systemic circulation.


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First Pass Effect

Drugs that are highly metabolized by the

liveror 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 orpre-systemic elimination.

BP Metabolism

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