BIOTRANSFORMASI Aznan Lelo, Tri Widyawati Dep. Farmakologi & Terapeutik, Fakultas Kedokteran Universitas Sumatera Utara 25 Januari 2008, KBK, FK USU

Pharmacokinetic o absorption o distribution  BIOTRANSFORMATION o elimination

Elimination Drug Metabolism (Biotransformation) Excretion

Drug Metabolism The chemical modification of drugs with the overall goal of getting rid of the drug change –size –lipid solubility –charge or polarity Enzymes are typically involved in metabolism Drug Metabolism More polar (water soluble) Drug Excretion

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

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

BA : %ase obat yang secara utuh mencapai sirkulasi umum untuk melakukan kerjanya PENGARUH FPE TERHADAP BIO-AVAILABILITY ( KETERSEDIAAN BIOLOGIS) proses absorpsi penguraian di dalam usus (kuman-kuman) atau dindingnya FPE di hati REAKSI TRANSFORMASI PEROMBAKAN PENGGABUNGAN/KONJUGASI OKSIDASI: - Enzim oksidatif : sitokromP450(CYP450) - Alkohol,aldehide, asam dan zat hidrat arang dioksidasi menjadi CO2 dan air REDUKSI: - Kloralhidrat direduksi menjadi trikloretanol - Vitamin C menjadi dehidroaskorbat HIDROLISA: Molekul obat mengikat 1 molekul air dan pecah menjadi 2 bagian -Penyabunan ester oleh esterase - Gula oleh karbohidrase ASETILASI : - Asam cuka mengikat gugus amino yang tak dapat dioksidasi, mis. Asetilasi dari sulfonamida dan piramidon SULFATASI : - Asam sulfat mengikat gugus OH fenolis menjadi ester, mis. Estron (sulfat) GLUKURONIDASI : - Asam glukoronat membentuk glukuronida dengan cara mengikat gugus-OH (fenolis) pula (morfin, kamfer,dsb) dan trikloretanol METILASI: - Molekul obat bergabung dengan gugus-CH3, misalnya nikotinamid dan adrenalin menjadi derivat metilnya. Molekul obat bergabung dengan molekul yang terdapat dalam tubuh sambil mengeluarkan air

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, not seen with the parent drug

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.

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 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 amitrptiline bioavailability is higher

Enzyme Inhibition and Inactivation Enzyme Inhibitor compound that slows or blocks enzyme catalysis Why inhibit an enzyme? Enzyme substrate beneficial (essential), but depleted low levels of GABA lead to seizures—therefore inhibit GABA aminotransferase to prevent degradation of GABA Enzyme product harmful excess uric acid leads to gout—inhibition of xanthine oxidase prevents conversion of xanthine to uric acid

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

Reversible Enzyme Inhibitors K i = k off / k on therefore smaller K i = better inhibitor competitive inhibitor inhibitor binds at active site; blocks substrate binding inhibitor may be metabolized easier to design non-competitive inhibitor binds at different (allosteric) site changes enzyme conformation to prevent binding or turnover difficult to design

Irreversible Enzyme Inhibitors Drug molecule (or a portion thereof) becomes irreversibly (covalently) bound to enzyme Affinity labeling agent –Reactive compound similar to natural enzyme substrate –Reacts with nucleophile in active site: acylation, alkylation Enzyme selectivity Binding specificity

examples with regards to enzymes other than cytochrome P450s –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 »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 –example: lignocaine toxicity can occur when patients are given a beta- blocker which reduces liver blood flow

Oral Administration Intestines Liver Intravenous Administration Metabolism

Drug biotransformation The process of drug metabolism involving the breakdown, detoxification and removal of chemicals from the body

Drug biotransformation Liver is primary site of drug metabolism Oxidation: drug conversion to more water soluble compound Iso-enzymes Metabolite formation

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

Hepatic ‘First-Pass’ Metabolism 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

Factors Affecting Biotransformation

Factors influencing drug biotransformation Age Pregnancy Disease Genetics

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

Disease altered liver enzymes –liver disease most decrease enzymes some may increase other diseases that decreased liver enzymes –hypothyroid –hypoxemia –malnutrition

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

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

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

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

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

Kecepatan Metabolisme obat Dosis Obat