Conceptual Subdivisions of Pharmacology Jamaluddin Shaikh, Ph.D. Associate Professor School of Pharmacy, University of Nizwa Lecture 4 September 18, 2013

Conceptual Subdivisions of Pharmacology

Conceptual Subdivisions of Pharmacology Pharmacokinetics: Pharmacokinetics includes the processes of drug absorption, distribution, metabolism and elimination “What the body does to the drug.”  Pharmacodynamics: Pharmacodynamics is the study of the biochemical and physiological effects of drugs “What the drug does to the body.” The individual differences in drug disposition and effect may account for interpatient variability in drug response

Conceptual Subdivisions of Pharmacology

Conceptual Subdivisions of Pharmacology Drug disposition: Human drug transporters include efflux or uptake transporters. Transporters Efflux transporters: Active efflux is a mechanism responsible for extrusion of toxic substances and antibiotics outside the cell; this is considered to be a vital part of xenobiotic metabolism. P-glycoprotein Transporters Uptake transporters: Promote hepatic uptake and metabolism, and/or the renal secretion of organic acids or bases.

Conceptual Subdivisions of Pharmacology The liver is the predominant site of drug metabolism. However, the liver and kidney cooperate to eliminate most orally administered drugs. Elimination pathways typically involve a series of gene products including: - Various enzymes for metabolism of the drug and its metabolite(s). Possible transporters for excretion. Genetic variability in proteins involved with drug metabolism and excretion can lead to individual differences in response to drugs.

Conceptual Subdivisions of Pharmacology While the disposition of many prescription drugs is influenced by drug transporters, the effects of genetic variations on human drug responses is less in membrane transporters than variations in drug metabolizing enzymes. Therefore our emphasis will be more on drug metabolism. Drug metabolism

Drug Biotransformation Phase 1 Cytochrome P-450: The oxidative metabolism of most drugs is mediated by the CYP enzyme system located in the liver and several other organs, including the lung and GI-tract. Over 70% of drugs are metabolized by CYP450 gene products. CYP enzymes are a superfamily distributed across the living kingdom. The gene families that exist in humans encode more than 50 individual CYP genes and enzymes. Three gene families are most important in humans (CYP1, CYP2, and CYP3).

Drug Biotransformation CYP450 Nomenclature: Example: CYP3A4 The first letters — CYP — is the abbreviation for Cytochrome P-450. The number 3 designates the family. The letter A designates the sub-family. The last number designates Specific gene/enzyme.

Drug Biotransformation CYP450 enzymes: The Cytochrome P-450 1, 2, and 3 gene families (CYP1, CYP2, and CYP3) encode the enzymes involved in the majority of human drug metabolism reactions. The following are responsible for metabolizing most of the clinically important drugs: CYP1A2 CYP2C19 CYP2A6 CYP2D6 CYP2B6 CYP3A4 CYP2C9 CYP3A5 These 8 CYP gene products participate in drug metabolism and most are polymorphic.

Drug Biotransformation CYP450 enzymes:

Drug Biotransformation Metabolizer Classifications: For enzymes such as those encoded by CYP-450 genes, phenotypes can range from poor, intermediate, extensive, and ultra-rapid metabolizers. Usually the phenotypes reflects the number of variant alleles of the gene that are present.

Drug Biotransformation Metabolizer Classifications: 1. Poor Metabolizer: A poor metabolizer (PM) has two defective alleles and lacks the functional enzyme. The drug accumulates so that concentration in the blood is elevated, often to toxic levels. 2. Intermediate Metabolizer: An intermediate metabolizer (IM) is either: 1. Heterozygous for one functional and one deficient allele. 2. Carries two partially defective alleles which cause reduced metabolism. The drug accumulates so that concentration in the blood is somewhat elevated.

Drug Biotransformation Metabolizer Classifications: 3. Extensive Metabolizer: An extensive metabolizer (EM) has two normal alleles. This is often the majority of the population and someone who is an extensive metabolizer is considered "normal." The blood concentration of the drug is likely at normal levels 4. Ultra-Rapid Metabolizer: An ultra-rapid metabolizer (URM) has duplicated or multi-duplicated functional alleles with a substantially higher metabolic capacity. The drug is metabolized rapidly causing the blood concentration to remain low