Exam 4 Study Guide - Lecture 29 PDF
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This study guide for lecture 29 details drug metabolism and disposition, including xenobiotics, routes of administration, and phases of metabolism. It covers various aspects of drug metabolism and pharmacokinetics.
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2 Lecture 29: Intro to Drug Metabolism & Disposition Xenobiotics Xenobiotics are chemical substances that are not endogenously found in the human body. These compounds can include drugs, environmental pollutants, pesticides, food additives, and other synthetic chemicals. The bod...
2 Lecture 29: Intro to Drug Metabolism & Disposition Xenobiotics Xenobiotics are chemical substances that are not endogenously found in the human body. These compounds can include drugs, environmental pollutants, pesticides, food additives, and other synthetic chemicals. The body often processes xenobiotics through metabolic pathways designed to detoxify and eliminate them, primarily in the liver. Major Routes of ADME 1. Oral RouteWithoutFirst Pass Metabolism Drug (P) gets ingested and goes into the GIT. Due to low absorption, the drug predominantly stays within the GI and gets excreted asunmetabolizeddrug (P) in the feces. 2. Oral RouteWithFirst Pass Metabolism Drug (P) gets ingested and goes into the GIT ⇒ gets absorbed through the intestinal wall ⇒ travels to liver via hepatic portal vein ⇒ some drug (P) turn into metabolites (M) via hepatocyte-mediated enzymatic reactions. The mixture of drug and metabolite(s) travels through the hepatic vein and gets distributed to target organs ⇒ excreted via urine and feces as a mixture of (P + M). 3. IV Route Drug enters body via IV ⇒ systemic circulation ⇒ circulation reaches liver and kidneys and undergo hepatic & renal metabolism ⇒ drug gets eliminated via urine and bile. 3 The Routes of Drug Elimination Definition of Drug Metabolism Drug metabolism- the biological process by which the body chemically alters drugs into metabolites. In most cases, metabolites have a lower therapeutic efficacy than the parent drug. 4 However,prodrugs, which are drugs thatrequiremetabolism in order to be biologically active in the body, have reduced or no efficacy compared to their metabolites. Depending on the therapeutic circumstance, drug metabolism may increase, decrease, or not cause adverse drug reactions (ADRs) and toxicity. Impact of Drug Metabolism Drug metabolism reactions often determine the intensity and duration of action of drugs. They play a key role in detoxification and toxification, depending on the scenario. Drug metabolism rates often depend on doses and administration frequency. Impact of Drug Pharmacokinetics - Rates of absorption, distribution, and elimination. Impact of Drug Pharmacodynamics - Target binding, duration of action, efficacy, and potency. Impact of ADRs & Toxicity - Can be increased, decreased, or not changed due to metabolism. Overview of the Phases of Drug Metabolism Phase 0 - Involves cellular uptake of drugs by membrane-bound transporters. 5 Phase I - Introduce small, hydrophilic functional groups, such as OH, NH2, SH, O, or COOH. This results in a small increase in water solubility Phase II - Involve conjugation to transfer an large, ionized group to a drug. Results in a large increase of water solubility. These reactions can occur w/o prior phase I. Phase III - Cellular efflux of drugs by membrane-bound transporters. Phase I Drug-Metabolizing Enzymes Oxidation-Based Enzymes - Cytochrome P450 (P450, CYP) - Flavin-containing monooxygenase (FMO) - Alcohol dehydrogenase (ADH) - Aldehyde dehydrogenase (ALDH) - Molybdenum hydroxylase (AOX & XDH) - Monoamine oxidase (MAO) Reduction-Based Enzymes - Aldo-keto reductase (AKR) - Quinone oxidoreductase (NQO) - Dihydropyrimidine dehydrogenase (DPYD) Hydrolysis-Based Enzymes - Carboxylesterase (CES) - Paraoxonase (PON) - Epoxide hydrolase (EPHX) 6 Phase II Drug-Metabolizing Enzymes UDP-glucuronosyltransferases (UGTs) Sulfotransferases (SULTs) Glutathione s-transferases (GSTs) N-acetyltransferases (NATs) Methyltransferases - Thiopurine S-methyltransferase (TPMT) - Catechol O-methyltransferase (COMT) Phase 0 Uptake Transporters Organic anion transporters (OATs) Organic anion transporting polypeptides (OATPs) Organic cation transporters (OCTs) Solute carrier organic anion transporters (SLCOs) Phase III Efflux Transporters ATP-binding cassette transporters (ABCs) - P-glycoprotein (P-gp) - Multidrug resistance 1 (MDR1, ABCB1) - Multidrug resistance-associated protein 2 (MRP2, ABCC2) - Breast cancer resistance protein (BCRP, ABCG2) Solute carrier transporters (SLCOs) 7 Subcellular Location of ADME Proteins Cell membrane - All uptake & efflux transporters. Endoplasmic reticulum - Phase I ⇒ P450, FMO, NQO, EPHX. - Phase II ⇒ UGTs, GSTs, TPMT. Cytosol - Phase I ⇒ AOX, NQO, EPHX, AHD, ALDH. - Phase II ⇒ GSTs, SULTs, NATs, TPMT. Mitochondria - Phase I ⇒ MAO, ALDH2. - Phase II ⇒ NATs
