Chapter 2 Pharmacokinetics Absorption, Distribution, Metabolism, and EliminationWhat happens to drugs?Absorption and DistributionRoutes of Drug AdministrationMembrane TransportPowerPoint PresentationInfluence of PH on Drug Absorption and DistributionChemistry ReviewSlide 9Metabolism and BiotransformationWhere does the metabolism occur?MetabolismTypes of MetabolismSlide 14P450 Enzyme InductionSlide 16Slide 17Phase I Metabolic ReactionsPhase II Metabolism: ConjugationSlide 20Drug Elimination (Please Review Kidney Physiology)Drug EliminationSlide 23NephronGlomerular Filtration (GF)Tubular secretionTubular ReabsorptionThe Importance of Renal Function in Drug TherapyPharmacogeneticsAcetylation Polymorphism: Slow or Rapid AcetylatorsMetabolism of Isoniazide N-acetyltransferase type 2 (NAT2)Chapter 2Pharmacokinetics Absorption, Distribution, Metabolism, and EliminationWhat happens to drugs?•Traverse membranes to reach their site of action •Transported throughout the circulatory system •End up at tissues and organs where their presence is beneficial•End up in some areas where their presence may be detrimentalAbsorption and DistributionRoutes of Drug Administration•Orally (PO)•Intramuscularly (IM)•Intravenously (IV)•Subcutaneously (SQ)Membrane TransportChallenges:Membranes are composed of lipid bilayersMembranes are nonpolarMembranes’ pores are small (most drugs >1 nm diameter)The perfect drug:UnchargedNonpolarLow MWHigh lipid solubilityFigure 2-2 Increased lipid solubility influences the amount of drug absorbed from the stomach for three different barbiturates. The number above each column is the oil/water equilibrium partition coefficient. The compounds have roughly equivalent pKa values and so the degree of ionization is similar for all three drugs.Downloaded from: StudentConsult (on 20 July 2005 11:00 PM)© 2005 Elsevier Lipid Solubility and Drug AbsorptionInfluence of PH on Drug Absorption and DistributionChemistry Review•Acid or Base?RCOOH, RNH+3RCOO-, RNH2•Which one is nonionized in low pH (i.e., stomach)?•Which one is nonionized in high pH (i.e., intestine)?Figure 2-3 Degree of acidic or basic drug in nonionized (uncharged) form (HA, acid; B, base) at different pH values, with pH expressed relative to the drug pKa.Downloaded from: StudentConsult (on 20 July 2005 11:00 PM)© 2005 Elsevier The Fraction of Nonionized Acid and Base in different PH Acids:RCOOH, RNH+3Bases:RCOO-, RNH2Metabolism and BiotransformationWhere does the metabolism occur?•Liver•Other tissues: GI, lungs, kidney, skin, etc.Metabolism•Disappearance of a drug when it is changed chemically into a metabolite •Alteration of the chemical structure of the drug by an enzyme from a nonpolar, lipid-soluble compound to a more polar form that is more water solubleTypes of Metabolism•Oxidation •Conjugation •Reduction •HydrolysisFigure 2-7 Simplified model of cytochrome P450 mixed-function oxidase reaction sequence. D is the drug undergoing oxidation to produce DOH. Molecular oxygen serves as the final electron acceptor. Flavin protein cofactor (Fp) systems are involved at several sites. The iron of the cytochrome P450 is involved in binding oxygen and electron transfer with changes in valence state.Downloaded from: StudentConsult (on 20 July 2005 11:00 PM)© 2005 Elsevier OxidationCytochrome P450123P450 Enzyme Induction•Enhancing the rate of P450 enzymes synthesis or reducing its rate of degradation•Many drugs, environmental chemicals, air pollutants, and components of cigarette smoke •P450 isoforms: CYP2B1, CYP1A1, CYP3As, CYP2E1, etc.Figure 2-10 Example of enzyme induction. Zoxazolamine administered by intraperitoneal injection to rats. For induction studies, phenobarbital or 3,4-benzo[a]pyrene was injected twice daily for 4 days before injection of zoxazolamine.Downloaded from: StudentConsult (on 20 July 2005 11:01 PM)© 2005 Elsevier Enzyme Induction: ZoxazolamineDownloaded from: StudentConsult (on 20 July 2005 11:01 PM)© 2005 Elsevier Reduction and Hydrolysis ReactionsPhase I Metabolic Reactions•Oxidation •Reduction •Hydrolysis •Convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (-OH, -NH2,-SH)•If phase I metabolites are not sufficiently polar, they will undergo phase II metabolismPhase II Metabolism:Conjugation•Coupling the drug molecule to an endogenous (glucuronic acid, sulfuric acid, acetic acid, etc) substituent group •The resulting product will have greater water solubility •Other modifications that lead to enhanced renal or biliary eliminationFigure 2-9 Sequence of reactions for conjugation of salicylic acid to form salicyl phenolic glucuronide. P, Phosphate. The glucuronic acid must first be activated, with glucose-1-phosphate coupling with high-energy UTP (uridine triphosphate) to UDP-glucose followed by oxidation to UDP-glucuronic acid before conjugation can occur.Downloaded from: StudentConsult (on 20 July 2005 11:01 PM)© 2005 Elsevier ConjugationDrug Elimination(Please Review Kidney Physiology)Drug Elimination•Hepatic Clearance•Biliary Clearance•Renal ClearanceFigure 2-12 Summary of renal clearance (CL)r mechanisms. Cp, Renal arterial blood concentration of drug; f, fraction of drug in plasma not bound; GFR, glomerular filtration rate of drug; TR, tubular reabsorption of drug; TS, tubular secretion of drug.Downloaded from: StudentConsult (on 20 July 2005 11:01 PM)© 2005 Elsevier Renal Clearance/EliminationCLrNephronGlomerular Filtration (GF)•A linear increase with increasing plasma drug concentrations in the renal artery•GF is 125 ml/min and total renal plasma flow is 650 to 750 ml/min•Only a small fraction of the total renal plasma flow is cleared of drug on each pass through the kidneys•Because albumin and other plasma proteins normally do not pass through the glomeruli, drug molecules that are bound to these proteins are retainedTubular secretion •An active process that occurs in the proximal tubule•Involves active transport by carriers•Since there are a limited number of carriers, the process can become saturated. •The volume of plasma that can be cleared per unit time by tubular secretion varies with the concentration of drug in plasma. •This is in contrast to glomerular filtration, where the volume filtered per unit time is independent of plasma concentration. •Tubular secretion removes bound and free drug because tubular transit time can be sufficiently long, such