Section 5 - (PT2) Pharmacokinetics

Click to edit Master title style Click to edit Master text styles Second level Third level Fourth level Fifth level Click to edit Master title style Click to edit Master text styles Second level Third level Fourth level Fifth level Principles of Pharmacology and Toxicology (BIOL3020) Drug Elimination e  Drug Metabolism This involves the enzymatic conversion of one chemical entity (drug) to another (metabolite) Metabolism converts drugs into more polar chemicals This conversion may lead to a pharmacologically active metabolite Or may lead to a toxin being formed Drug Polar Chemical (Active metabolite or Toxin) Elimination Drug Metabolism  The P450 Pathway . / Drug Metabolism The OH serves as the point of attack for phase II system to attach a substituent such as glucuronide by another enzyme UDP-glucuronyl transferase This forms an inactive, readily excretable product Both phases increase water solubility  The P450 Family of Enzymes There are three main cytochrome P450 enzymes (CYP1, CYP2 and CYP3) There are different subclasses within each Different drugs are substrates for different P450 enzymes Isoenzyme P450 Drug CYP1A1 Theophylline CYP1A2 Caffeine, paracetamol, tacrine, theophylline CYP2A6 Methoxyflurane CYP2C8 Taxol CYP2C9 Ibuprofen , phenytoin , tolbutamide , warfarin CYP2C19 Omeprazole CYP2D6 Clozapine , codeine, debrisoquine, metoprolol CYP2E1 Alcohol, enflurane , halothane CYP3A4/5 Ciclosporin, losartan, nifedipine , terfenadine From Pichard et al. (1995) Predictability of drug metabolism from in vitro studies. In Alvan G et al. (eds) COST B1 conference on variability and specificity in drug metabolism. European Commission, Luxembourg, pp. 45-56. Variations in P450 Activity Environmental Influence Enzyme inhibitors and inducers are present in the diet and environment Grapefruit juice inhibits drug metabolism Brussels sprouts and cigarette smoke induce P450 enzymes. Metabolism can alter drug properties Aspirin inhibits some platelet functions and has anti-inflammatory activity It is hydrolysed to salicylic acid, which has anti-inflammatory but not antiplatelet activity Metabolism can convert inactive prodrugs into active drugs or toxins See table 8.3 in text and www.studentconsult.com. Some drug metabolites are the active form Some metabolites are toxins Some metabolites have the same activity as the original drug Drug and Metabolite Elimination Renal excretion is the most common form of elimination About 20 of drug, cross the glomerular filter of the kidney. 80 is transported from the peritubular capillaries to the tubules by active transport Especially weak acids and bases  Active Transport Tubule Glomerular filter Drug and Metabolite Elimination Lipid-soluble drugs are passively reabsorbed by diffusion across the tubule back to the blood are not efficiently excreted in the urine. Because of pH partition, weak acids are more rapidly excreted in alkaline urine, and vice versa.  Active Transport Tubule Urine pH affects Elimination and Drug Response Alkaline urine will cause acidic drugs to be eliminated faster Urine pH affects drug response and plasma concentration Pharmacokinetic Plots Toxicokinetics v  Stine and Brown (2006) Principles of Toxicology Toxicokinetics p  Stine and Brown (2006) Principles of Toxicology