METABOLISME DEPARTMENT OF PHARMACOLOGY AND THERAPEUTIC UNIVERSITAS SUMATERA UTARA dr. Yunita Sari Pane

Pharmacokinetic   absorption   distribution   BIOTRANSFORMATION   elimination

Oral Administration Intestines Liver Intravenous Administration Metabolism

GI: Biliary-Fecal Route liver bile gall bladder GI track blood Enterohepatic cycle

GI: Biliary-Fecal Route n lipid soluble drugs have prolonged effects

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

First Pass Effect n pass through liver before reaching circulation n undergo metabolism by liver

Biotransformation chemical alteration of drug

Biotransformation Biotransformation n change size size lipid solubility lipid solubility charge or polarity charge or polarity

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

Factors Affecting Biotransformation

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

Disease n altered liver enzymes liver disease liver disease – most decrease enzymes – some may increase

Disease n other diseases that decreased liver enzymes hypothyroid hypothyroid hypoxemia hypoxemia malnutrition malnutrition

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

Biotransformation

Decreased Activity of Liver Enzymes n decreased rate of biotransformation can result in toxic effects

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

Hepatic ‘First-Pass’ Metabolism n Affects orally administered drugs n Metabolism of drug by liver before drug reaches systemic circulation n Drug absorbed into portal circulation, must pass through liver to reach systemic circulation n May reduce availability of drug

Elimination Elimination Drug Metabolism (Biotransformation) Excretion

Drug Metabolism n The chemical modification of drugs with the overall goal of getting rid of the drug n Enzymes are typically involved in metabolism Drug Metabolism More polar (water soluble) Drug Excretion

ABSORPTION METABOLISM ELIMINATION Phase I Phase II Phase I Phase II Drug Conjugate Drug metabolite with Conjugate Drug metabolite with Conjugate modified activity modified activityDrug Inactive drug Conjugate Inactive drug Conjugate metabolite metaboliteDrug LipophilicHydrophilic LipophilicHydrophilic

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

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

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

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

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

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

Alteration in “first pass metabolism” (note: high clearance drug have > 30% extraction from hepatic blood (F 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 vice-versa a drug that inhibits hepatic metabolism will increase bioavailability of high clearance drug (provided it is metabolised by the enzyme(s) inhibited) and vice-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

Enzyme Inhibition (drugs that reduce hepatic blood flow also inhibit metabolism of high clearance drugs) (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 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 enzyme inhibition is immediate, and on cessation of inhibitor, reversion to normal is immediate

examples: 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

examples with regards to enzymes other than cytochrome P450s example 1: allopurinol example 1: allopurinol – is a xanthine oxidase inhibitor (used as an anti-gout agent) – also inhibits metabolism of cytotoxic agent 6- mercaptopurine (6-MP) – therefore concurrent use of allopurinol and 6-MP leads to elevated plasma levels of 6-MP and toxicity

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

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 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 beta-blocker which reduces liver blood flow example: lignocaine toxicity can occur when patients are given a beta-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.