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59-291 Section 1, Lecture 4 Phase I reactions-oxidative occur in the endoplasmic reticulum of liver (microsomal fractions) - catalyzed by the microsomal P450 monooxygenase system 1 Phase I Biotransformation • Oxidative reactions – Catalyzed by enzymes of microsomal fraction (ER) of liver • Microsomal cytochrome P450 monooxygenase 2 P450 Enzyme Complex Microsomal cytochrome P450 monooxygenase system is a family of enzymes that biotransforms many drugs Fe3+ Fe2+ Hemoprotein Only Heme-Fe2+ can bind O=O Fe3+ Fe2+-O=O 3 -many drugs affect the activity of p450 enzymes: induction or inhibition -phenobarbital and rifampin 2 drugs that induce increased transcription and translation of the P450 genes Drugs combine with P450 enzymes and block their activity -net result all drugs metabolized by the P450 system are destroyed and excreted faster What are the consequences? 4 Hydrolytic reactions: Cytoplasmic Enzymes Catalyze the hydrolysis (add H2O) or reduction of drugs Reductive Drugs 5 Phase II Biotransformation • Conjugation Reactions with endogenous substances – Acetylation • N- acetyltransferase uses acetyl CoA as a source of acetate – Glucuronide formation • Glucuronosyltransferase conjugates glucuronate molecule with a drug – Sulfation • Sulfotransferase sulfonates several drugs. The sulfate metabolites are active 6 Phase II Biotransformation -here drugs are conjugated (added) to other molecules Acetylation- by N-acetyltransferase enzymes Glucuronide formation- adds carbohydrate making drugs more soluble- via glucosyltransferases 7 Sulfation- catalyzed by sulfotransferases- sulfated drugs retain bioactivity O R O S OH O 8 Genetic variations in drug biotransformation -Acetylation slow r/r(Middle Eastern) ; fast r/R or R/R alleles (Japanese) -P450- genetic variations in the CYP2D6 4-hydroxylase -Extensive metabolizers; or -poor metabolizers no pain relief from codeine prodrug for morphine catalyzed by CYP2D6 4-hydroxylase Other genetic variations- 1:3000 occurrence atypical cholinesterasewill not metabolize topical anasthetic succinycholine these individuals may stay “frozen” for days or weeks- need to be screened for this enzyme 9 Practice questions (to be discussed in the class) • 1000 g of a drug is injected to patient and Cp0 was measured, which is 10 mg/L. • Where is this drug concentrated mainly? Why? • Vd=Dose/Cp0 >> Vd= (1g)1000/10= 100 • Since Vd is very large for this drug, more than total volume of body compartment, it is concentrated mostly in the cells due to ion trapping. 10 • Identify the phase and type of the following drug transformation – Drug-OCH3 Drug-OH + CH2O • Phase I, O-Dealkylation – Drug- NH2 + AcetylcoA-CO-CH3 coA-SH + Drug-NH-CO-CH3 Acetyl • Phase II, Acetylation – Drug-CH2CH3 Drug-CHOH- CH3 • Phase I, Aliphatic hydroxylation 11