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UCSD BIMM 118 - Lecture 3

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Drug MetabolismPhases of Drug MetabolismSlide 3Drug Metabolism - Phase IDrug Metabolism - OxidationSlide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Drug Metabolism - ReductionSlide 16Drug Metabolism - Phase IDrug Metabolism - Phase IIDrug Metabolism - GlucuronidationSlide 20Slide 21Slide 22Slide 23Drug Metabolism - SulfationDrug Metabolism - AcylationDrug Metabolism - Other conjugationsDrug Metabolism - Phase I & IIDrug Action: Receptor TheorySlide 29BIMM118Drug Metabolism•Most metabolic products are less pharmacologically activeImportant exceptions:•Where the metabolite is more active (Prodrugs, e.g. Erythromycin-succinate (less irritation of GI) --> Erythromycin)•Where the metabolite is toxic (acetaminophen)•Where the metabolite is carcinogenic•Close relationship between the biotransformation of drugs and normal biochemical processes occurring in the body:–Metabolism of drugs involves many pathways associated with the synthesis of endogenous substrates such as steroid hormones, cholesterol and bile acids –Many of the enzymes involved in drug metabolism are principally designed for the metabolism of endogenous compounds–These enzymes metabolize drugs only because the drugs resemble the natural compoundBIMM118Phases of Drug Metabolism•Phase I Reactions–Convert parent compound into a more polar (=hydrophilic) metabolite by adding or unmasking functional groups (-OH, -SH, -NH2, -COOH, etc.)–Often these metabolites are inactive–May be sufficiently polar to be excreted readily•Phase II Reactions–Conjugation with endogenous substrate to further increase aqueous solubility–Conjugation with glucoronide, sulfate, acetate, amino acid–Phase I usually precede phase II reactionsLiver is principal site of drug metabolism:–Other sites include the gut, lungs, skin and kidneys–For orally administered compounds, there is the “First Pass Effect”•Intestinal metabolism•Liver metabolism•Enterohepatic recycling•Gut microorganisms - glucuronidasesBIMM118Drug MetabolismBIMM118Drug Metabolism - Phase I•Phase I Reactions–Oxidation–Reduction–Hydrolytic cleavage–Alkylation (Methylation)–Dealkylation–Ring cyclization–N-carboxylation–Dimerization–Transamidation–Isomerization–DecarboxylationBIMM118Drug Metabolism - OxidationTwo types of oxidation reactions:–Oxygen is incorporated into the drug molecule (e.g. hydroxylation)–Oxidation causes the loss of part of the drug molecule (e.g. oxidative deimination, dealkylation)Microsomal Mixed Function Oxidases (MFOs)•“Microsomes” form in vitro after cell homogenization and fractionation of ER–Rough microsomes are primarily associated with protein synthesis –Smooth microsomes contain a class of oxidative enzymes called •“Mixed Function Oxidases” or “Monooxygenases”–These enzymes require a reducing agent (NADPH) and molecular oxygen (one oxygen atom appearing in the product and the other in the form of water)BIMM118Drug Metabolism - Oxidation•MFO consists of two enzymes:–Flavoprotein, NADPH-cytochrome c reductase•One mole of this enzyme contains one mole each of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD)•Enzyme is also called NADPH-cytochrome P450 reductase–Cytochrome P450•named based on its light absorption at 450 nm when complexed with carbon monoxide •is a hemoprotein containing an iron atom which can alternate between the ferrous (Fe++) and ferric (Fe+++) states •Electron acceptor•Serves as terminal oxidase•its relative abundance compared to NADPH-cytochrome P450 reductase makes it the rate-limiting step in the oxidation reactionsBIMM118Drug Metabolism - Oxidation•Humans have 18 families of cytochrome P450 genes and 43 subfamilies:–CYP1 drug metabolism (3 subfamilies, 3 genes, 1 pseudogene)–CYP2 drug and steroid metabolism (13 subfamilies, 16 genes, 16 pseudogenes)–CYP3 drug metabolism (1 subfamily, 4 genes, 2 pseudogenes)–CYP4 arachidonic acid or fatty acid metabolism (5 subfamilies, 11 genes, 10 pseudogenes)–CYP5 Thromboxane A2 synthase (1 subfamily, 1 gene)–CYP7A bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus (1 subfamily member)–CYP7B brain specific form of 7-alpha hydroxylase (1 subfamily member)–CYP8A prostacyclin synthase (1 subfamily member)–CYP8B bile acid biosynthesis (1 subfamily member)–CYP11 steroid biosynthesis (2 subfamilies, 3 genes)–CYP17 steroid biosynthesis (1 subfamily, 1 gene) 17-alpha hydroxylase–CYP19 steroid biosynthesis (1 subfamily, 1 gene) aromatase forms estrogen–CYP20 Unknown function (1 subfamily, 1 gene)–CYP21 steroid biosynthesis (1 subfamily, 1 gene, 1 pseudogene)–CYP24 vitamin D degradation (1 subfamily, 1 gene)–CYP26A retinoic acid hydroxylase important in development (1 subfamily member)–CYP26B probable retinoic acid hydroxylase (1 subfamily member)–CYP26C probabvle retinoic acid hydroxylase (1 subfamily member)–CYP27A bile acid biosynthesis (1 subfamily member)–CYP27B Vitamin D3 1-alpha hydroxylase activates vitamin D3 (1 subfamily member)–CYP27C Unknown function (1 subfamily member)–CYP39 7 alpha hydroxylation of 24 hydroxy cholesterol (1 subfamily member)–CYP46 cholesterol 24-hydroxylase (1 subfamily member)–CYP51 cholesterol biosynthesis (1 subfamily, 1 gene, 3 pseudogenes) lanosterol 14-alpha demethylaseBIMM118Drug Metabolism - Oxidation•Induction of P450 enzymes:–PPAR (peroxisome proliferator activated receptor) ligands (e.g.clofibrate)–CYP1 family are induced by aromatic hydrocarbons (cigarette smoke; charred food)–CYP2E enzymes induced by ethanol–CYP2B enzymes induced 40-50 fold by barbiturates•Polymorphisms cause differences in drug metabolism:–CYP2C19 has a polymorphism that changes the enzyme's ability to metabolize mephenytoin (a marker drug). In Caucasians, the polymorphism for the poor metabolizer phenotype is only seen in 3% of the population. However, it is seen in 20% of the asian population. => It is important to be aware of a person's race when drugs are given that are metabolized differently by different populations•P450s and drug interactions:–Barbiturates induce CYP2B => increased metabolism of other drugs–Antifungals (e.g. ketoconazole) inhibit fungal CYP51 and unintentionally also human CYP3A4 => reduced metabolism of other drugs–Grapefruit juice contains a CYP3A4 inhibitor =>12 fold increase in some drug concentrationsCYP3A4 Substrates: • Acetominophen


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UCSD BIMM 118 - Lecture 3

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