PHC511 Drug Metabolism I Lecture Topics PDF

Phase I “Basic Principles of DM” MOOC  Comprehend, apply, and evaluate the main concepts and principles of drug metabolism.  Identify and characterize all of major metabolites of a given drug and specific enzymes responsible for its metabolism. The Fate of a Drug...

Phase I “Basic Principles of DM” MOOC  Comprehend, apply, and evaluate the main concepts and principles of drug metabolism.  Identify and characterize all of major metabolites of a given drug and specific enzymes responsible for its metabolism. The Fate of a Drug DOSE Pharmaceutics ABSORPTION MOST TISSUES NONSPECIFIC BINDING PLASMA PROTEIN DISTRIBUTION FREE BOUND BIOPHASE ELIMINATION RECEPTOR BINDING METABOLISM RENAL EXCRETION EFFECT Pharmacokinetics Pharmacodynamics  Drug at site of administration 1. Absorption Drug in plasma 2. Distribution Drug/metabolites 3. Metabolism in tissues 4. Elimination Drug/metabolites in urine, feces, bile  Drug Metabolism It is the metabolic breakdown of drugs by living organisms or foreign compounds [xenobiotics] mostly in the liver (enzymatic processes). It often converts lipophilic compounds to hydrophilic products that are more readily excreted.. It may convert procarcinogen into toxic mutagenic compounds. Individual variation greatly impact metabolism (genetic diff., physiol. factors). Metabolism of one xenobiotic may influence another’s metabolism This will help synthesize new more safe drugs Xenobiotics Metabolism in non-hepatic tissue Drugs Intestinal mucosa Other foreign non-essential compounds Kidney Lung First-pass metabolism: Bacteria in GIT Xenobiotic metabolized before reaching general circulation First-pass metabolism: A. Lung metabolism (inhaled drugs). B. Intestinal mucosa, GI bacteria Consequences of Drug Metabolism 1. Termination of drug action 2. Activation of prodrug 3. Bioactivation and toxication 4. Carcinogenesis Effect of drug metabolism Active drug inactivation Inactive Drug Inactive prodrug activation Active Drug Inactive metabolite  Lipid Solubility R-H Chemical hook activation Procarcinogen Carcinogen Pathways of metabolism Phase I: Functionalization reaction, new polar groups such as CO2H, OH or NH2 are introduced or unveiled from pre-existing via oxidation, reduction. or hydrolysis. Phase II: Conjugation reaction link an endogenous moiety to the original drug or to the phase I metabolite (GSH, sulfate, glycine, glucuronic acid) to produce more polar metabolites unable to cross membranes, and therefore, be actively excreted. Phase III: Some conjugated xenobiotics may be further processed, to be recognised by efflux transporters and pumped out of cells for elimination. Example: Hydrophobic drug More Hydrophilic drug Renal excretion Drug metabolism was thought detoxification, not absolutely true !!!!! Implications For Drug Metabolism: 1. Termination of drug action. 2. Activation of prodrug. 3. Bioactivation and toxification. 4. Carcinogenesis. Two xenobiotic categories are hardly subject to metabolic transformations: So, spread 1- Hydrophilic compounds the word (Saccharine, strong acids Take care or bases). 2. Highly lipophilic polyhalogenated xenobiotics such as some insecticides e.g. DDT. Many metabolic reactions don’t lead to inactivation and detoxication. Some metabolite are as active as the parent drug. Others are reactive and bind covalently to soluble or membrane proteins, enzymes, DNA (mutagenic and carcinogenic compounds). Lethal synthesis: The metabolic conversion of the nontoxic Parathion to its oxygenated isostere paraoxon, a potent acetylcholinesterase inhibitor.  Major Sites of Metabolism Drug metabolism occurs in every tissue (e.g. gut, lung, kidney). However, the major Drug Metabolizing Enzymes (DMEs) are the highest levels in the liver, the major organ of metabolic clearance. High: liver. Medium: lung, kidney, intestine. Low : skin, testes, placenta, adrenals. Very low: CNS. Extrahepatic microsomal enzymes (oxidation, conjugation) LIVER Is the chief organ for metabolism due to: 1. High blood Hepatic microsomal enzymes flow through (oxidation, conjugation) the liver. 2.Hepatocytes Hepatic non-microsomal enzymes contain (acetylation, sulfation, GSH, numerous alcohol/aldehyde dehydrogenase, metabolic hydrolysis, ox/red) enzymes