Younggil kwon handbook of essential Pharmacokine(BookZZ org)

Handbook of Essential Pharmacokinetics, Pharmacodynamics and Drug Metabolism for Industrial Scientists Handbook of Essential Pharmacokinetics, Pharmacodynamics and Drug Metabolism for Industrial Scientists Younggil Kwon, Ph.D Bioneer Life Science San Diego, California Kluwer Academic Publishers New York, Boston, Dordrecht, London, Moscow eBook ISBN: Print ISBN: 0-306-46820-4 0-306-46234-6 ©2002 Kluwer Academic Publishers New York, Boston, Dordrecht, London, Moscow All rights reserved No part of this eBook may be reproduced or transmitted in any form or by any means, electronic, mechanical, recording, or otherwise, without written consent from the Publisher Created in the United States of America Visit Kluwer Online at: and Kluwer's eBookstore at: http://www.kluweronline.com http://www.ebooks.kluweronline.com To my wife, Heekyung, and two daughters, Jessica and Jennifer Preface In the pharmaceutical industry, the incorporation of the disciplines of pharmacokinetics, pharmacodynamics, and drug metabolism (PK/PD/DM) into various drug development processes has been recognized to be extremely important for appropriate compound selection and optimization During discovery phases, the identification of the critical PK/PD/DM issues of new compounds plays an essential role in understanding their pharmacological profiles and structure-activity relationships Owing to recent progress in analytical chemistry, a large number of compounds can be screened for their PK/PD/DM properties within a relatively short period of time During development phases as well, the toxicology and clinical study designs and trials of a compound should be based on a thorough understanding of its PK/PD/DM properties During my time as an industrial scientist, I realized that a reference work designed for practical industrial applications of PK/PD/DM could be a very valuable tool for researchers not only in the pharmacokinetics and drug metabolism departments, but also for other discovery and development groups in pharmaceutical companies This book is designed specifically for industrial scientists, laboratory assistants, and managers who are involved in PK/PD/DM-related areas It consists of thirteen chapters, each of which deals with a particular PK/PD/DM issue and its industrial applications Chapters and 12 in particular address recent topics on higher throughput in vivo exposure screening and the prediction of pharmacokinetics in humans, respectively Chapter covers essential information on drug metabolism for industrial scientists The important equations are highlighted and the commonly used terms in PK/PD/DM are summarized in a glossary at the end of the book I hope that all those who consult this book find it useful as an easy-to-understand reference for identifying, analyzing, and addressing PK/PD/DM-related issues in their respective fields of research Younggil Kwon, Bioneer Life Science Co San Diego, California vii viii Preface Acknowledgments I would like to express my gratitude to Drs Bonnie Mangold and Francis Tse and Ms Elina Dunn for their valuable comments and suggestions, and to Mr Michael F Hennelly for his encouragement and support Contents Introduction Pharmacokinetic Study Design and Data Interpretation 2.1 Intravenous Administration of Drugs 2.1.1 Utility of Intravenous Administration Studies 2.1.2 General Considerations for Intravenous Administration Studies 2.1.3 Sample Collection after Intravenous Administration 2.2 Oral Administration of Drug 2.2.1 Utility of Oral Administration Studies 2.2.2 General Considerations for Oral Administration Studies 2.2.3 Sample Collection after Oral Administration-Blood 2.3 Data Interpretation 2.3.1 Compartmental Approach 2.3.2 Noncompartmental Approach References 3 New Approaches for High Throughput In Vivo Exposure Screening 29 3.1 N-in-1 (Cassette or Cocktail) Dosing 3.2 Postdose Pooling (or Cocktail Analysis) 3.3 AUC Estimation from One Pooled Sample 3.4 Continuous Sampling Method References Absorption 4 6 8 18 28 29 31 31 33 33 35 4.1 Rate-Limiting Steps in Oral Drug Absorption 4.1.1 Dissolution Rate-Limited Absorption 4.1.2 Membrane Permeation Rate-Limited Absorption 4.2 Factors Affecting Oral Absorption 4.2.1 Physiological Factors ix 35 35 37 38 38 x Contents 4.2.2 Physiochemical Factors of Drugs 4.2.3 Effects of pH and pKa of a Drug on Absorption (pH-Partition Theory) 4.2.4 Partition and Distribution Coefficients 4.3 Bioavailability 4.3.1 Definition 4.3.2 Factors Affecting Bioavailability and the First-Pass Effect 4.3.3 Estimating the Extent of Absorption 4.3.4 Estimating the Rate of Absorption 4.4 Enterohepatic Circulation 4.4.1 Recognizing Enterohepatic Circulation 4.4.2 Pharmacokinetic Implications of Enterohepatic Circulation 4.4.3 Physicochemical Properties of Compounds for Biliary Excretion 4.4.4 Measuring Clearance in the Presence of Enterohepatic Circulation 4.4.5 Investigating Enterohepatic Circulation 4.5 Fecal Excretion of Drugs and Coprophagy 4.6 Lymphatic Absorption References 40 41 44 45 45 46 47 54 66 67 68 68 68 69 70 70 71 Distribution 5.1 Definition 5.1.1 Proportionality Factor 5.1.2 Pharmacokinetic Implications of the Volume of Distribution 5.1.3 Summary of the Characteristics of the Volume of Distribution 5.2 Different Volume Terms 5.2.1 Apparent Volume of Distribution of the Central Compartment 5.2.2 Volume of Distribution at Steady State 5.2.3 Volume of Distribution at Pseudodistribution Equilibrium 5.3 Estimating the Volume of Distribution 5.3.1 Apparent Volume of the Central Compartment 5.3.2 Volume of Distribution at Steady State 5.3.3 Volume of Distribution at Pseudodistribution Equilibrium 5.3.4 Differences among Vc , Vss , and Vβ 5.3.5 Relationships among Vc , Vss , Vβ , Cls , and Cld References 73 73 73 74 75 75 76 76 79 80 80 80 81 81 82 82 Clearance 6.1 Definition 6.1.1 Proportionality Factor 6.1.2 Apparent Volume of Reference Fluid Cleared of a Drug per UnitTime 6.2 Systemic (Plasma) Clearance 83 85 83 83 83 xi Contents 6.2.1 Estimation 6.2.2 Relationship between Systemic Clearance and the Volume of Distribution 6.2.3 Relationship between Systemic Clearance and the Terminal Half-Life 6.2.4 Amount of Drug Eliminated from the Body 6.3 Organ Clearance 6.3.1 Hepatic Clearance 6.3.2 Biliary Clearance 6.3.3 Renal Clearance 6.4 Relationship between Systemic Blood and Organ Clearances 6.5 Apparent Clearance following Oral Dosing 6.6 Distributional Clearance 6.7 Blood vs Plasma Clearances 6.7.1 Blood Clearance 6.7.2 Plasma Clearance 6.7.3 Relationship between Blood and Plasma Clearances 6.7.4 Relationship between Blood and Plasma Concentrations 6.7.5 Clearance Based on Unbound Drug Concentration in Plasma 6.7.6 Relationship among Blood, Plasma, and Unbound Drug Clearances References Protein Binding Definition 7.2 Estimating the Extent of Protein Binding 7.2.1 Equilibrium Dialysis 7.2.2 Ultrafiltration 7.2.3 Microdialysis 7.3 Pharmacokinetic and Pharmacodynamic Implications of Protein Binding 7.3.1 Effects on Clearance 7.3.2 Effects on the Volume of Distribution 7.3.3 Effects on Half-Life 7.3.4 Effects on Pharmacological Efficacy 7.3.5 Effects on Drug-Drug Interaction 7.4 Factors Affecting Protein Binding 7.5 Nonlinearity of Plasma Protein Binding 7.6 Plasma vs Serum and I n Vitro v s E x Vivo Protein Binding Measurements 7.7 Protein Binding in Tissues 7.7.1 General Trends in Drug Binding to (Muscle) Tissues 7.7.2 Pharmacokinetic Implications of Tissue Binding 7.8 Species Differences in Protein Binding References 85 86 86 86 87 89 94 95 98 99 99 100 100 100 100 101 102 102 103 105 105 107 109 110 111 112 112 114 115 115 115 116 117 117 118 118 119 119 119 276 Appendix which is true only when the plasma drug concentration vs time curve after intravenous injection can be properly described by a one-compartment model Otherwise, t1/2 is a function of Vβ , the volume of distribution at the terminal phase, not Vss, the volume of distribution at steady state (Vβ > Vss) Oral Bioavailability AUCiv,0 - ∞ : AUC from time zero to infinity after intravenous bolus injection AUCpo,0 – ∞ : AUC from time zero to infinity after oral administration Div: Intravenous dose Dpo: Oral dose F: Oral bioavailability Mean Residence Time AUC0 – ∞: AUC from time zero to infinity regardless of the route of administration AUMC0 – ∞: AUMC from time zero to infinity regardless of the route of administration MRT: Mean residence time 10 Mean Absorption Time MAT: Mean absorption time MRTiv, MRTpo: MRT after intravenous bolus injection or oral administration, respectively 11 Plasma Drug Concentration at Steady State after Continuous Intravenous Infusion Cp,ss: Plasma drug concentration at steady state after continuous intravenous infusion Cls: Systemic plasma clearance k0: Infusion rate 277 Appendix 12 Metabolite Kinetics ,m: AUC from time zero to infinity of the drug and its metabolite, respectively regardless of the route of administration Cls, Clm: Systemic plasma clearance of the drug and its metabolite, respectively fm: Fraction of the dose of the drug transformed to the metabolite AUC -∞,AUC -∞ 13 Relationship between BloodandPlasma Concentrations C b: Crbc: Cp: Hct: Drug concentration in blood Drug concentration in red blood cells Drug concentration in plasma Hematocrit 14 Amount of a Drug Absorbed into the Portal Vein after Oral Administration MASS BALANCE METHOD: Aa: Amount of the drug absorbed into the portal vein after oral administration AUCpo,pv AUCpo,sys: AUC of the drug from time zero to infinity in the portal vein and systemic blood (or plasma when blood concentrations are the same to plasma concentrations) after oral administration, respectively Qpv: Portal vein blood flow rate CLEARANCE METHOD Clb: Systemic blood (or plasma when blood concentrations are the same as plasma concentrations) clearance AUCpo,pv: AUC of drug in portal vein blood (or plasma when blood concentrations are the same as plasma concentrations) after oral administration 278 Appendix B Typical Pharmacokinetic Issues and Their Potential Causes Route of administration Oral administration Issues Potential causes Low bioavailability Limited absorption Poor aqueous solubility (dissolution rate-limited) Poor membrane permeability (permeation rate-limited) Efflux by P-glycoprotein or multidrug resistance-associated protein in the intestine Microfloral metabolism in the intestine, e.g., reduction of azo compounds Extensive first-pass effect Presystemic intestinal metabolism (CYP3A4, CYP2C9, UDPGT, etc) Presystemic hepatic clearance (metabolism and/or biliary excretion) Enterohepatic circulation Enterohepatic circulation of parent drug Biliary excretion of metabolites followed by subsequent conversion to the parent drug in intestinal lumen (e.g., biliary excretion of glucuronide conjugates of drug and subsequent deconjugation in gut lumen) Variability in pH in the stomach Delayed gastric emptying Slow absorption of drug The rate of absorption of drug from the intestine is slower than the rate of elimination from body Nonlinear absorption and/or clearance Limited aqueous solubility Saturation of active transporters in enterocytes during absorption Saturation of protein binding Nonlinear absorption and/or clearance Saturation of efflux mechanism(s) in enterocytes during absorption Saturation of clearance mechanisms Induction Autoinduced metabolism Induction of P-glycoprotein for biliary and/or intestinal excretion Multicompartmental distribution Multiple peaks in exposure profile Flip-flop kinetics (a longer terminal half-life after P.O than I.V dosing) Less than dose-proportional increase in exposure as dose increases More than dose-proportional increase in exposure as dose increases Decreasing exposure after multiple doses Intravenous administration Biexponential declining of exposure profile Nonlinear protein binding Saturated protein binding at high concentrations during the initial phase Nonlinear metabolism Product inhibition on metabolism of parent drug during the later phase 279 Appendix Route of administration Issues Sustained or elevated exposure at the beginning and then declining Short half-life Longer half-lives at higher dose levels Potential causes Nonlinear clearance Substrate inhibition of metabolism during the initial phase Precipitation of drug at the injection site and subsequent dissolution Rapid clearance Extensive metabolism, biliary and/or renal elimination Low protein binding Small volume of distribution Confinement of drug in plasma More extensive protein binding in plasma than in tissues Nonlinear clearance Limitation of assay sensitivity at low concentrations (no dose dependent half-life changes with better assay sensitivity) Product inhibition C References for Laboratory Animal Experiments Animal Physiology Altman P L and Dittmer D S., Respiration and Circulation, Federation of American Society for Experimental Biology, Bethesda, 1970 Dressman J B., Comparison of canine and human gastrointestinal physiology, Pharm Res 3: 123-131, 1986 Frank D W., Physiological data of laboratory animals, in E C Melby Jr and N H Altman (eds.), Handbook of Laboratory Animal Science, Vol II CRC Press, Cleveland, 1974, pp 23-64 Havenaar et al., Biology and husbandry of laboratory animals, in L F M van Zutphen, V Baumans and A C Beynen (eds.), Principles ofLaboratory Animal Science: A Contribution to the Humane Use and Care of Animals and to the Quality of Experimental Results, Elsevier, New York, 1993, pp 17-74 Kararli T T., Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals, Biopharm Drug Dispos 16: 351-380, 1995 Lindstedt S L and Calder III W A., Body size, physiological time and longetivity of homeothermic animals, Q Rev Biol 56: 1-16,1981 Animal Handling Andrews E J et al., Report of the AVMA panel on Euthanasia, J A V M A 202: 229-249, 1993 Coates M E., Feeding and watering, in A A Tuffery (ed.), Laboratory Animals: An Introductionfor New Experiments, 2nd Ed., John Wiley & Sons, New York, 1995, pp 107–128 Gregory J A., Principles of animal husbandry, in A A Tuffery (ed.), Laboratory Animals: A n Introduction for New Experiments, 2nd Ed., John Wiley & Sons, New York, 1995, pp 87–106 Laboratory Animal, Reference Series [The Laboratory Mouse (T L Cunliffe-Beamer, 1998), The Laboratory Guinea Pig (L Terril, 1998), The Laboratory Hamster and Gerbil (K Field, 1998), The Laboratory Cat (B J Martin, 1998), The Laboratory Rat (P Sharp and M LaRegina, 1998), and The Laboratory Rabbit (M A Suckow and F A Douglas, 1997)], CRC Press, Boca Raton, FL 280 Appendix Mann M D et al., Appropriate animal numbers in biomedical research in light of animal welfare considerations, Lab Animal Sci 41: 6–14, 1991 Morton D B et al., Removal of blood from laboratory mammals and birds, First report of the BVA/FRAME/RSPCA/UFAW joint working group in refinement, Lab Animals 27: 1–22, 1993 Morton D B and Griffiths P H M., Guidelines on the recognition of pain, distress and discomfort in experimental animals and an hypothesis for assessment, Vet Record 16: 431–436, 1985 Runciman W B et al., A sheep preparation for studying interactions between blood flow and drug disposition I: physiological profile, Br J Anaesth 56: 1015–1028, 1984 Animal Disease Models Cawthorne M A et al., Adjuvant induced arthritis and drug-metabolizing enzymes, Biochem Pharmacol 25: 2683–2688, 1976 Cypess R H and Hurvitz A I., Animal models, in E C Melby Jr and N H Altman (eds.), Handbook of Laboratory Animal Science, Vol 11, CRC Press, Cleveland, 1974, pp 205–228 Gurley B J et al., Extrahepatic ischemia-reperfusion injury reduces hepatic oxidative drug metabolism as determined by serial antipyrine clearance, Pharm Res 14: 67–72, 1997 Ramabadran K and Bansinath M., A critical analysis of the experimental evaluation of nociceptive reactions in animals, Pharm Res 3: 263–270, 1986 Sofia R D., Alteration of hepatic microsomal enzyme systems and the lethal action of non-steroidal anti-arthritic drugs in acute and chronic models of inflammation, Agents Actions 7: 289–297, 1977 Transgenic Animal Models Cameron E R et al., Transgenic science, Br Vet J 150: 9–24, 1994 Nebert D W and Duffy J J., How knockout mouse lines will be used to study the role of drug-metabolizing enzymes and their receptors during reproduction and development, and in environmental toxicity, cancer and oxidative stress, Biochem Pharmacol 53: 249–254, 1997 Animal Surgery and Experiments General Surgery, Sample Collection, and Anesthesia Beyner A C et al., Design of animal experiments, in L F M van Zutphen, V Baumans and A C Beynen (eds.), Principles of Laboratory Animal Science: A Contribution to the Humane Use and Care of Animals and to the Quality of Experimental Results, Elsevier, New York, 1993, pp 209–240 Castaing D et al., Hepatic and Portal Surgery in the Rat, Masson, Paris, 1980 Chaffee V W., Surgery of laboratory animals, in E C Melby Jr and N H Altman (eds.), Handbook of Laboratory Animal Science, Vol I, CRC Press, Cleveland, 1974, pp 231–274 Cocchetto D M and Bjornsson T D., Methods for vascular access and collection of body fluids from the laboratory rat, J Pharm Sci 72: 465–492, 1983 Heavner J E., Anesthesia, analgesia and restraint, in W I Gay (ed.), Methods of Animal Experimentation, Academic Press, New York, pp 1–36, 1986 McGuill M W and Rowan A N., Biological effects of blood loss: implications for sampling volumes and techniques, ILAR News 31: 5–20, 1989 Scobie-Trumper P., Animal handling and manipulations, in A A Tuffery (ed.), Laboratory Animals; An Introduction for Experiments, 2nd Ed., John Wiley & Sons, New York, 1995, pp 233–254 Sharp P E and LaRegina M C., Veterinary Care, pp 105–107, Experimental Methodology, pp 129–159, The Laboratory Rat, CRC Press, New York, 1998 Steinbruchel D A., Microsurgical procedures in experimental research, in P Svendsen and J Hau (eds.), Handbook of Laboratory Animal Science, Vol I: Selection and Handling of Animals in Biomedical Research, CRC Press, London, 1974, pp 371–382 Tuffery A A., Laboratory Animals: An Introduction for Experiments, 2nd Ed., John Wiley & Sons, New York, 1995 Appendix 281 Wilsson-Rahmberg M et al., Method for long-term cerebrospinal fluid collection in the conscious dog, J Inves Sur 11: 207–214, 1998 Metabolism/Liver Perfusion/Portal Vein Cannulation/Liver Injury Effeney D J et al., A technique to study hepatic and intestinal drug metabolism separately in the dog, J Pharmacol Exp Ther 221: 507–511, 1982 Gerkens J F et al., Hepatic and extrahepatic glucuronidation of lorazepam in the dog, Hepatology 1: 329–335, 1981 Gores G J et al., The isolated perfused rat liver: conceptual and practical considerations, Hepatology 6: 511–517, 1986 Iwasaki T et al., Regional pharmacokinetics of doxorubicin following hepatic arterial and portal venous administration: evaluation with hepatic venous isolation and charcoal hemoperfusion, Cancer Res 58: 3339–3343, 1998 Maza A M et al., Influence of partial hepatectomy in rats on the activity of hepatic microsomal enzymatic systems, Eur J Drug Metab Pharmacokinet 22: 15–23, 1997 Plaa G L., A four-decade adventure in experimental liver injury, Drug Metab Rev 29: 1–37, 1997 Sahin S and Rowland M., Development of an optimal method for the dual perfusion of the isolated rat liver, J Pharmacol Toxicol Methods 39: 35–43, 1998 Sloop C H and Krause B R., Portal and aortic blood sampling technique in unrestrained rats, Physiol Behav 26: 529–533, 1981 Urban E and Zingery A A., A simple method of cannulation of the portal vein and obtaining multiple blood samples in the rat, Experienta 37: 1036–1037, 1981 Absorption/Enterohepatic Circulation/lntestinal Perfusion Fujieda Y et al., Local absorption kinetics of levofloxacin from intestinal tract into portal vein in conscious rat using portal-vein concentration difference, Pharm Res 13: 1201– 1204, 1996 Kuipers F et al., Enterohepatic circulation in the rat, Gastroenterology 88: 403–411, 1985 Pang K S et al., Disposition of enalapril in the perfused rat intestine-liver preparation: absorption, metabolism, and first-pass effect, J Pharmacol Exp Ther 233: 788–795, 1985 Tabata K et al., Evaluation of intestinal absorption into the portal system in enterohepatic circulation by measuring the difference in portal-venous blood concentrations of diclofenac, Pharm Res 12: 880-883,1995 Tsutsumi H et al., Method for collecting bile with a T-cannula in unrestrained conscious Beagles, Exp Anim 45: 261–263, 1996 Windmueller H G and Spaeth A E., Vascular autoperfusion of rat small intestine in situ Methods Enzymol 77: 120–129, 1981 Bioavailability Dressman J B and Yamada K., Animal models for oral drug absorption, in P G Welling, F L S Tse, and S V Dighe (eds.), Pharmaceutical Bioequiualence, Vol 48, Dekker, New York, 1991, pp 235–266 Humphreys W G et al., Continuous blood withdrawal as a rapid screening method for determining clearance and oral bioavailability in rats, Pharm Res 15: 1257–1261, 1998 Krishnan T R et al., Use of the domestic pig as a model for oral bioavailability and pharmacokinetic studies, Biopharm Drug Dispos 15: 341–346, 1994 Lukas G et al., The route of absorption of intraperitoneally administered compounds, J Pharmacol Exp Ther 178: 562–566, 1971 Microdialysis Deguchi Y et al., Muscle microdialysis as a model study to relate the drug concentration in tissue interstitial fluid and dialysate, J Pharmacobio-Dyn 14: 483–492, 1996 282 Appendix Evrard P A et al., Simultaneous microdialysis in brain and blood of the mouse: extracellular and intracellular brain colchicine disposition, Brain Res 786: 122– 127, 1998 Telting-Diaz M et al., Intravenous microdialysis sampling in awake, freely-moving rats, Anal Chem 64: 806–810, 1992 Terasaki T et al., Determination of in vivo steady-state unbound drug concentration in the brain interstitial fluid by microdialysis, Int J Pharm 81: 143–152, 1992 Placenta Perfusion Poranen A K et al., Vasoactive effects and placental transfer of nifedipine, celiprolol, and magnesium sulfate in the placenta perfused in vitro, Hyper Preg 17: 93–102, 1998 Schneider H et al., Transfer across the perfused human placenta of antipyrine, sodium and leucine, Am J Obstet Gynecol 114: 822–828, 1972 Miscellaneous Beyssac E., The unusual routes of administration, Eur J Drug Metab Pharmacokinet 21: 181–187, 1996 Cocchetto D M and Wargin W A,, A bibliography for selected pharmacokinetic topics, Drug Intel Clin Pharm 14: 769–776, 1980 Ramabadran K and Bansinath M., A critical analysis of the experimental evaluation of nociceptive reactions in animals, Pharm Res 3: 263–270, 1986 D Abbreviations α: Aa: Ac(t): Ae : Ae,0 -∞: Am(t): A(t): ADME: AUC: AUCm: AUCia: AUCip: AUCiv: AUCpo: AUCpo,pv : AUCpo,vc : AUMC: β: exponential coefficient of a biexponential differential equation total amount of a drug absorbed into the portal vein after oral administration amount of the drug in the central compartment at time t amount of the drug excreted unchanged in the urine cumulative amount of a drug excreted unchanged in the urine from time zero to infinity amount of the metabolite produced from the drug in the body at time t after intravenous administration amount of a drug in the body at time t absorption, distribution, metabolism, and excretion area under the plasma drug concentration vs time curve area under the plasma metabolite concentration vs time curve area under the plasma drug concentration vs time curve after intraarterial injection area under the plasma drug concentration vs time curve after intraportal vein (or intraperitoneal) injection area under the plasma drug concentration vs time curve after intravenous injection area under the plasma drug concentration vs time curve after oral administration AUC of a drug in portal vein blood (or plasma) after oral administration AUC of a drug in vena cava blood (or plasma) after oral administration area under the first-moment curve of plasma drug concentration vs time curve exponential coefficient of a biexponential differential equation Appendix C: Cavg,ss: Cb(t): Ce(t): Cin,ss: Cint: Ci,u: Cm(t): Cmax: Cout,ss: Cp(O): Cp(t): Cp,ss: Crbc: Css: Ct(t): CT(t): Cu(t): Clb: Clbl: Cld: Clg: Clh: Cli,h: Clm: Cl(m): Clnr: Clother Clp: Clr: Cls: Clu: CYP: Dia: Dip: Div: Dn: Dpo: E: 283 concentration average drug concentration in plasma during a dosing interval at steady state after multiple dosing of a fixed drug dose at the same dosing interval drug concentration in blood at time t drug concentration at the effect site at time t drug concentration in blood entering the eliminating organ at steady state drug concentration in the gastrointestinal fluid unbound drug concentration within hepatocytes or available for metabolizing enzyme(s) and/or biliary excretion metabolite concentration in plasma at time t the highest drug concentration in plasma after extravascular administration drug concentration in blood leaving the eliminating organ at steady state imaginary drug concentration in plasma at time zero after intravenous injection of a drug, estimated by extrapolation of the plasma drug concentration-timecurve to time zero drug concentration in plasma at time t plasma drug concentration at steady state after intravenous infusion drug concentration in red blood cells drug concentration at steady state average drug concentration in the extravascular space, into which the drug distributes at time t average drug concentration in the peripheral (tissue) compartment at time t concentration of drug not bound to blood components at time t systemic blood clearance biliary clearance distributional clearance intestinal clearance hepatic (blood) clearance intrinsic hepatic clearance metabolic drug clearance to produce a particular metabolite systemic metabolite clearance nonrenal clearance clearance other than via the metabolic pathway of a drug to a particular metabolite plasma clearance renal clearance systemic (plasma) clearance drug clearance based on unbound drug concentration cytochrome P450 intraarterial dose intraportal vein (or intraperitoneal) dose intravenous dose dispersion number oral dose extraction ratio or drug effect 284 Eg: Eh: E(t): EC50: Emax: F: Fa: fe: Fg: Fh: F1: fm: Fr: Fs: f u: fu,b: fu,t: GFR: Hct: IC50: k: k10: k12,k21: ka: Km: km: k(m): k0: MAT: MIT: Appendix intestinal extraction ratio hepatic extraction ratio pharmacological effect of drug at time t concentration of drug showing 50% of its maximum effect maximum effect of drug (oral) bioavailability fraction of the dose absorbed into gastrointestinal epithelial cells (enterocytes) from the intestinal lumen after oral administration of a drug fraction of the dose excreted unchanged in the urine fraction of the amount of a drug absorbed into enterocytes after oral administration of a drug that escapes the presystemic intestinal elimination fraction of the amount of a drug entering the liver that escapes elimination by the liver on a single pass through the organ, or the fraction of a drug entering the liver that escapes the presystemic hepatic elimination after oral administration fraction of the amount of a drug entering the lung that escapes elimination by the lung on a single pass through the organ, or the fraction of a drug entering the lung that escapes the presystemic pulmonary elimination after oral administration fraction of the dose metabolized fraction of the amount of a drug reabsorbed from the renal distal tubule after being filtered and secreted in the glomerulus and the proximal tubule fraction of a dose reaching the systemic circulation as unchanged drug after oral administration (considering first-pass effect by the lung as well) ratio between the unbound and total drug concentrations in plasma ratio between the unbound and total drug concentrations in blood average ratio between unbound and total drug concentrations in tissues (extravascular space) glomerular filtration rate hematocrit concentration of drug showing 50% of its maximum inhibitory effect first-order rate constant first-order elimination rate constant from the central compartment first-order distribution rate constants from the central to the peripheral compartments or from the peripheral to the central compartments, respectively first-order absorption rate constant Michaelis–Menten constant or the apparent Michaelis–Menten constant for metabolizing enzyme(s) and/or biliary excretion first-order rate constant associated with the formation of metabolites from the parent drug first-order rate constant associated with the elimination of metabolites drug infusion rate or zero-order rate constant mean absorption time of a drug after oral administration mean input time of a drug Appendix 285 MRT: MRTabs: mean residence time of a drug MRT for the absorption of drug molecules dosed in solution into the systemic circulation MRTdisint: MRT for the disintegration of the orally dosed solid dosage form of a drug to a suspension MRTdiss: MRT for the dissolution of the orally dosed solid drug particles to solution MRTiv: MRT after intravenous injection MRTpo: MRT after oral administration P450: cytochrome P450 Papp: apparent membrane permeability Pint: intestinal membrane permeability Q: blood flow rate Qh: hepatic blood flow rate portal vein blood flow rate Qpv: Qr: renal blood flow rate R: accumulation factor effective surface area of intestinal membranes available for drug absorpSint: tion half-life of a drug during the terminal phase of plasma drug concentrat1/2 tion–time profile the last time point when a quantifiable drug concentration can be tlast: measured time at which Cmax is observed following extravascular administration of tmax: drug apparent volume of distribution of a drug V: apparent volume of distribution at the β phase (or terminal phase) based Vβ : on drug concentration in plasma apparent volume of the central compartment based on the drug concenVc: tration in plasma Vextrapolated: initial dilution volume of a drug Vm: Vmax: Vp: Vss: V(t): Vt: V T: λ: apparent volume of distribution of metabolite maximum rate of enzymatic reaction or the apparent maximum rate of metabolizing enzyme(s) and/or biliary excretion actual physiological volume of plasma apparent volume of distribution at steady state based on the drug concentration in plasma apparent volume of distribution of a drug at time t actual physiological volume of extravascular space (blood cells, interstitial fluids, and tissues) outside the plasma into which the drug distributes apparent volume of the peripheral (tissue) compartment of drug the negative slope of the terminal phase of a plasma drug concentration– time profile on a semilogarithmic scale INDEX Absorption, 35, 279 Absorption rate constant, 24, 57, 62 ABT, 129 Accumulation factor, 26 Acetonitrile,64,154 Acetyl-coenzymeA, 140 Active secretion, 96 Active transport, 65, 170 Acylglucuronide, 137 Acylmigration 137 ADH, 133 ADME,1 Ah receptor,164 AIC,17 Akaike informationcriterion, 17 Albumin,106,116 Alcoholdehydrogenase,133 Aldehydedehydrogenase,133 ALDH,133 Allometry,205 Allometricequation, 206 All-or-noneresponse, 190 α1-Acid-glycoprotein,106,116 α -Phase, 15 Amino acid conjugation, 143 1-Aminobenzotriazole,129 Anesthesia, 236, 278 Animal physiology, 227, 277 Animal surgery, 278 Antibody,151 Apparent membrane permeability, 63 Aqueous boundary layer, 61 Area under the curve, 18 Area under the first moment curve, 19, 21 Assay limitation, 27 Assaysensitivity,182 AUC, 19, 21 AUMC, 19 Autoinduction,164,183 Basolateralmembrane, 38 Batemanequation,55 β-Glucuronidase, 67, 140 β-Phase, 15 BHT,158 Biexponential equation, 14 Bile, 230 Bile-cannulated animal, 149 Biliary active transport system, 170 Biliary clearance, 94, 169 Biliaryexcretion, 169 Bioavailability, 23, 47, 279 Biofeedback,199 Biotransformation,121 Biphasicdecline, 15 Biphasicreceptors,198 Birth weight, 228 Blood clearance, 100 Blood collection, 5, Blood flow rate, 229 Bloodmetabolism, 146 Body fluid, 228 Body water, 229 Body weight, 228 Bolus injection, Brush border membrane, 38 Butylated hydroxytoluene, 158 Caco-2 cells, 62 Caffeine,158 Canalicular bile acid transporter, 170, 172 Canalicularmultispecific organic aniontransporter, 170,172 Carrier-mediated transport, 65,66, 183 Cassette dosing, 29 CBAT,170 Central compartment, 13, 75 Charcoal-broiledmeat, 158 Chloral hydrate, 236 287 288 Chronopharmacokinetics,186 Cigarettesmoking,158 Clearance, 21, 83 Clearance after oral dosing, 99 Clearancedefinition, 83 Clearancemethod, 50 Clockwisehysteresis, 203 clog P, 45 Cmax,56 cMOAT,170,172 Cocktail analysis, 31 Cocktail dosing, 29 Commonlog, 11 Compartment, Complexation,41 Conjugation, 139 Continuous sampling, 33 Coprophagy, 7, 70 Cosubstratedepletion, 16, 183 Counterclockwisehysteresis,203 Cp(0), Creatinineclearance, 98 Cruciferousvegetables,158 Crystallineforms,41 Ctlast, 21 Curve fitting, 55 CYP, 123 CytochromeP420, 125 CytochromeP450, 123 Cytochrome P450 isoforms, 126, 149 Cytosol, 123 Deconjugation, 139 Diazepam,236 Diffusional barrier, 46 Diffusionlayer,37 Dimethyl sulfoxide, 64, 153 Directresponse, 191 Disease model, 278 Dispersionmodel,91 Dissolution, 36 Dissolution rate-limited absorption, 35 Distal tubule, 96 Distribution, 73 Distributional clearance, 82, 99 Distributionalequilibrium,77 Distributioncoefficient,44 Distributionphase, 15 Dosedependency, 175 Dosing solution, Dosing volume, 4, 6, 234 Downregulation, 199 Druginteraction, 199 Dual agonistic receptors, 197 EC50 , 202 Effect compartment model, 201 Index Effectivepermeability,60 Effect site, 189 EHC, 66, 95 Eliminationphase, 15 EM, 156 Emax model, 194 Endocytosis,65 Endoplasmicreticulum,123 Enterohepatic circulation, 66, 95, 279 Equilibriumdialysis, 109 Esterase, 132 Extensivemetabolizer,156 Extracellularfluid, 234 Extractionratio, 88 Extrahepaticmetabolism, 145 Extravascular fluid, 78 Facilitated diffusion, 65 Fibrinogen, 106 Fick's principle, 50 First-order kinetics, 9, 176, 180 First-pass effect, 46 Flavin-containing monooxygenase, 129 Flip-flop kinetics, 57 FMO,129 Food, 7, 40 Futile cycling, 139 Gastric motility, 39 Gastric residence time, 39 Gastrointestinalflow,231 Gastrointestinal pH, 232 Gauge, 235 Genotyping, 155 GFR, 230 Globulins, 106 Glomerular filtration, 95 Glossary, 239 Glururondation, 135 Glutathione, 141 GlutathioneS-transferase, 141 gp-170,171 Gradedresponse,190 Grapefruitjuice, 158 GST,141 Gut sterilization, 69 Half life, 24, 75, 115 Heart rate, 230 Hematocrit, 101 Hepatic clearance, 89 Hepatocytes, 147,222 High throughput screening, 29 Hillequation, 195 Homeostaticresponse, 199 Housekeeper wave, 39 Hydrophilicity,40 Index Hysteresis, 203 IC50, 203 Incomplete absorption, 46 Indirectresponse,191 Indirect response model, 202 Inducingagents, 164 Induction, 163 Infusion, 4, 85 Inhibitory E max model, 196 Initial disappearance rates, 214 Intact nephron hypothesis, 98 Interstitial fluid, 78 Intestinalmetabolism,145 Intestinal microflora, 40 Intestinal perfusion, 59, 279 Intestinal secretion, 70 Intestinal surface area, 39 Intestinal transit time, 39 Intracellularfluid, 234 Intracellular space, 78 Intravenousadministration,3 Intrinsic hepatic clearance, 92 In vitro intrinsic hepatic clearance, 211 In vitro metabolism, 221 In vivo exposure screening, 29 In vivo hepatic clearance, 219 In vivo intrinsic hepatic clearance, 219 Ionizability, 40 Irreversible response,192 Ketamine,236 Km, 93, 213 Lagrange method, 21 Linear model, 194 Lineartrapezoidal method, 19 Lineweaver-Burkplot,216 Link model, 201 Lipophilicity,40 Lipoprotein,106,116 Liver injury, 279 Liver perfusion, 148, 279 Liver slices, 148, 222 Log-linearmodel, 194 Log trapezoidal method, 21 Loop of Henle, 96 Lumen, 38 Lymphatic absorption, 70 Lymphatic delivery, 54 Lymphflow,231 Lysosome, 123 MAO, 134 Mass balance, 49 Maximum life span, 209 3-MC,164 289 MDR, 171 Mean absorption time, 23, 24, 57 Mean residence time, 19, 23 Mechanism-basedinhibitor,129 Membranepermeability, 37 Membrane permeation rate-limited absorption, 37 Membrane transport mechanisms, 63 Metabolic activities, 232 Metabolicinduction,163 Metabolicratio, 157 Metabolism,121,279 Metabolite,162 Metabolitekinetics, 159 Methanol, 64, 154 Method of residuals, 55 3-Methylcholanthrene,164 Methohexitone, 236 Methyltransferase, 142 Mesenteric artery, 52 Mesenteric blood vessel, 38, 52 Michaelis-Mentenkinetics,176,213 Microdialysis,111,279 Microsomes, 123, 147, 150, 222 Microvillus,38 Midazolam,236 Migrating motility complex, 39 Mlog P, 45 MLP,209 MMC, 39 Model selection, 17, 198 Molecularsize, 41 Molecularweightthreshold, 170 Moment analysis, 18, 57 Monoamineoxidase,134 Monophasicdecline,11 MR, 157 MRM, 30 MRP, 171 MRT, 19 Multi compartment, 9, 12 Multidrugresistance,171 Multidrugresistance-associatedprotein,171 Multiple dosing, 25 Mutliple reaction monitoring, 30 Multiplereceptors, 197 N-Acetyltransferase,140 NADP, 124 NAT, 140 Naturallog, 11 Needle size, 235 Neoteny, 209 124 Nicotinamide-adenosine-dinucleotide-phosphate, N-in-1 dosing, 29 NOAEL, 187 Noncompartmentalapproach,18 Nonlinearprotein binding, 16, 117 290 Nonlinear pharmacokinetics,175 Nonspecific binding,222 No observed adverse effect level, 187 Nucleus, 123 One compartment model, Oral administration, Oral bioavailability,47 Organ clearance, 87 Organic solvent effects on metabolism, 153 P450,123 PAH, 164 PAPS, 139 Paracellular transport,65 Parallel-tube model,91,210 Particle size, 41 Partition coefficient,44 Passive diffusion,65 Pentobarbital, 236 Peripheral compartment, 13, 15, 75 Permeability,37 Permeation,37 Peroxisome proliferator activated receptor, 164 P-glycoprotein,171 Pharmacodynamics,1,189 Pharmacodynamicsmodels,193 Pharmacogenetics,155 Pharmacokinetic/pharmacodynamic models,191, 199 Pharmacokinetic study design, Pharmacokinetics,1 Pharmacokinetics models, 12 Pharmacokineticsprediction,205 Pharmacologicaleffects,190 PhaseI metabolism, 121, 123 PhaseII metabolism, 122, 135 Phenotyping,149 pH in the gastrointestinal tract, 39 3´-Phosphoadenosine-5´-phosphosulfate,139 pH-partitiontheory, 41 Physiologically based prediction,209 pKa, 42 Placentaperfusion, 280 Plasma clearance, 100 Plasma protein, 105, 229 PM,156 Polycyclic aromatic hydrocarbon, 158 Polymorphism,41, 155 Poormetabolizer, 156 Portal blood sampling, 51 Portal vein cannulation, 279 Postdose pooling, 31 PPAR, 164 Presystemic elimination, 46 Presystemic hepatic elimination,53 Presystemic intestinal elimination,49 Index Presystemic pulmonary elimination,53 Product inhibition, 182,224 Propofol, 236 Protein binding, 105 Protein binding inserum, 117 Protein binding in tissue, 118 Proteresis, 203 Proximal tubule, 96 Pseudodistribution equilibrium,77, 79 Pulmonary elimination, 53 Purified enzymes, 147 Rat, 235 Reabsorption, 96 Receptor theory, 191 Recombinant enyzmes, 147, 151 Rectal administration,54 Renal clearance, 95, 97 Renal metabolism,97, 146 Reversible response, 192 S9 fraction, 147, 150 Sample collection, 4, 7, 278 Sampling time points, 4, Schwarz criterion 18 Semilogarithmic scale,11 Sensitization,199 Sigmoidal Emax model, 195 Sinusoidal perfusion model,91 Solution, 36 Species differenceinprotein binding, 119 Spline method,21 ST, 137 Stereoisomerism,199 Steroid binding globulin, 106 Suicideinhibitor, 129 Sulfatase,140 Sulfotransferase,137 Surgery,278 Suspension,36,41 Systemic blood clearance, 98 Systemic clearance,85 Tachyphylaxis, 199 TEER, 64 Terminal half life, 3, 24, 25, 218 Terminal phase, 15, 75 Thiopental,236 Thiopentone, 236 Tight junction, 38 Timedependency, 176 Tissue compartment, 13, 15, 75 TK, 187 t max, 56 Tolerance, 199 Toxicokinetics,187 Transcortin,106 291 Index Transepithelial electrical resistance, 64 Transgenic animal model, 278 Triacetyloleandomycin, 164 Two compartment model, 12, 76 UDPGA, 135 UDPGT, 135 Ultrafiltration, 110 Unstirred water layer, 60 Up regulation, 199 Urethane, 236 Uridine diphosphate-glucuronic acid, 136 Uridine diphosphate-glucuronosyltransferase, 135 Urine, 230 Urine collection, Venous equilibrium model, 90 Villus, 38 Vitamin C, 158 Vmax , 93, 213 Volume o f distribution, 73 Volume of distribution at pseudodistribution equilibrium, 79, 81 Volume of distribution at steady state, 22, 76, 80 Volume of distribution in central compartment, 76, 80 Volume shift, 109 Water intake, Well-stirred model, 90, 210 Xylazine, 236 Zero-order kinetics, 176, 181