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Lecture 3 - Drug Metabolism Most metabolic products are...

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BIMM118 Drug Metabolism Most metabolic products are less pharmacologically active Important 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 compound
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BIMM118 Phases of Drug Metabolism Phase I Reactions Convert parent compound into a more polar (=hydrophilic) metabolite by adding or unmasking functional groups (-OH, -SH, -NH 2 , -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 reactions Liver 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 - glucuronidases
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BIMM118 Drug Metabolism
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BIMM118 Drug Metabolism - Phase I Phase I Reactions – Oxidation – Reduction Hydrolytic cleavage Alkylation (Methylation) – Dealkylation Ring cyclization – N-carboxylation – Dimerization – Transamidation – Isomerization – Decarboxylation
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BIMM118 Drug Metabolism - Oxidation Two 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)
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BIMM118 Drug 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
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