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METABOLISME

dr. Yunita Sari Pane

DEPARTMENT OF PHARMACOLOGY AND THERAPEUTIC UNIVERSITAS SUMATERA UTARA

Pharmacokinetic

absorption distribution

BIOTRANSFORMATION
elimination

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Intravenous Administration Oral Administration

Metabolism

Liver

Intestines

GI: Biliary-Fecal Route Biliaryliver blood bile gall bladder GI track

Enterohepatic cycle

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GI: Biliary-Fecal Route Biliarylipid soluble drugs have prolonged effects

Oral Drugs
enter stomach: highly acidic stomach: environment absorbed by GI tract into portal circulation of the liver first-pass effect first-

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First Pass Effect

pass through liver before reaching circulation undergo metabolism by liver

Biotransformation
chemical alteration of drug

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Biotransformation
change size lipid solubility charge or polarity

Sites of biotransformation
liver: greatest activity others intestines, kidneys, brain, & plasma

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Factors Affecting Biotransformation

Age
very young less developed enzyme system less developed blood brain barrier very old decreased GI absorption decreased renal clearance

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Disease
altered liver enzymes liver disease most decrease enzymes
some

may increase

Disease
other diseases that decreased liver enzymes hypothyroid hypoxemia malnutrition

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Other
genetic alterations or defects in enzymes metabolize drug more slowly or more rapidly

Biotransformation

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Decreased Activity of Liver Enzymes

decreased rate of biotransformation

can result in toxic effects

Metabolism (Biotransformation)
Two effects Transformation to less active metabolite Enhancement of solubility Liver = primary site Liver disease Slows metabolism Prolongs effects

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Hepatic First-Pass FirstMetabolism

Affects orally administered drugs Metabolism of drug by liver before drug reaches systemic circulation Drug absorbed into portal circulation, must pass through liver to reach systemic circulation May reduce availability of drug

Elimination

Elimination

Excretion

Drug Metabolism (Biotransformation)

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Drug Metabolism
The chemical modification of drugs with the overall goal of getting rid of the drug Enzymes are typically involved in metabolism
Drug
Metabolism

More polar (water soluble) Drug

Excretion

ABSORPTION

METABOLISM
Phase I Phase II Conjugate

ELIMINATION

Drug

Drug metabolite with modified activity Drug

Conjugate

Inactive drug metabolite Drug

Conjugate

Lipophilic

Hydrophilic

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METABOLISM REACTION
I. PHASE - I - Oxidation : Morphin, acetaminophen - Reduction : Chloramphenicol, Clonazepam - Hydrolisis : Aspirin, Lidocain

METABOLISM REACTION
II. PHASE- II PHASE- Conjugation : Morphin (process glucuroridation), INH (process acetilation), etc.

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Sites of Drug Metabolism

Metabolism occurs in many tissues E.g. brain, kidney, lung But mostly in the liver because all of the blood in the body passes through the liver.

Consequences Of Metabolism
Drug metabolism != Drug inactivation The metabolite may have Equal activity to the drug No or reduced activity Increased activity (Prodrugs) Toxic properties

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METABOLISM KINETIC
1.First order kinetic if drugs lower doses metabolism rapidly. 2.Zerro order kinetic if drugs higher doses metabolism slowly.

The Most Important Enzymes

Microsomal cytochrome P450 monooxygenase family of enzymes, which oxidize drugs Act on structurally unrelated drugs Metabolize the widest range of drugs.

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Alteration in first pass metabolism

(note: high clearance drug have > 30% extraction from hepatic blood (F < 0.7)) a drug that inhibits hepatic metabolism will increase bioavailability of high clearance drug (provided it is metabolised by the enzyme(s) inhibited) and vicevice-versa

Examples:

cimetidine inhibits CYP450s, therefore doubles oral propranolol bioavailability phenytoin induces enzymes, therefore decreases felodipine bioavailability acute alcohol intake inhibits a CYP, therefore amitriptiline bioavailability is higher

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Enzyme Inhibition

(drugs that reduce hepatic blood flow also inhibit metabolism of high clearance drugs) if this metabolic route is a major pathway of elimination, drug kinetics will change (increase Css and T(1/2)) and therefore drug response will change enzyme inhibition is immediate, and on cessation of inhibitor, reversion to normal is immediate

examples: metronidazole decreases clearance of warfarin by 40% cimetidine decreases clearance of phenytoin by 35% propranolo decreases clearance of lignocaine by 50% (by reducing hepatic blood flow) omeprazole decreases clearance of warfarin

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examples with regards to enzymes other than cytochrome P450s

example 1: allopurinol is a xanthine oxidase inhibitor (used as an anti-gout agent) anti also inhibits metabolism of cytotoxic agent 66mercaptopurine (6-MP) (6 therefore concurrent use of allopurinol and 6-MP leads to 6elevated plasma levels of 6-MP 6and toxicity

example 2: disulfiram inhibits aldehyde dehydrogenase therefore is used to give alcoholics a nasty "aldehyde reaction" when they take alcohol

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Alteration of liver blood flow:

for high first pass clearance drugs only, a fall in liver blood flow will cause a clear reduction in systemic clearance example: lignocaine toxicity can occur when patients are given a betabeta-blocker which reduces liver blood flow

Importance
Toxic drugs may accumulate Useful drugs may have no benefit because doses are too small to establish therapy A drug can be rapidly metabolized.

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