Advanced Methods of Pharmacokinetic and Pharmacodynamic Systems Analysis Volume 3 [book]

David Z. D'Argenio
2004 The International Series in Engineering and Computer Science  
Contributors Participants Index 197 211 221 239 255 275 295 305 317 vi PREFACE This volume is the third in the series "Advanced Methods of Pharmacokinetic and Pharmacodynamic Systems Analysis" sponsored by the Biomedical Simulations Resource (BMSR) at the University of Southern California as part of its dissemination activities. Through its support from the Division of Bioengineering at the National Institute of Biomedical Imaging and Bioengineering at the NIH, the BMSR develops novel methods
more » ... ops novel methods for biomedical modeling and simulation and distributes its knowledge and methodologies through its collaborative research projects, as well as via service, training and dissemination activities. The contributions to this volume are derived from the presentations made at the BMSR sponsored 10th Workshop on Advanced Methods of PK/PD Systems Analysis held in Marina del Rey, California on June 16 and 17, 2003. The chapters are arranged in three sections under the general headings: mechanism-based PK/PD; pharmacometrics; and pharmacotherapeutics. The first section includes contributions on drug absorption in the small intestine and on cellular metabolism of nucleoside analogues, followed by four chapters focusing on in vivo exposure-response modeling that include fundamental aspects of receptor theory and cellular signaling pathways in PK/PD model development. In the second section on pharmacometrics, new approaches are presented for population modeling, deconvolution, Bayesian computation, and visualization of gene expression data. The section on pharmacotherapeutics includes chapters on modeling resistance in antiretroviral therapy and on modeling HIV dynamics during long-term treatment, as well as chapters on deterministic and stochastic approaches to dose regimen design in chemotherapy, and on control of pharmacodynamic processes. I wish to express my gratitude to all the authors for their excellent contributions to this volume. These researchers, as well as others who have contributed to our previous meetings, are at the forefront of innovation in pharmacokinetics/pharmacodynamics and its application to drug development. In addition I would like to recognize Marcos The extent and rate of drug absorption are strongly modulated by the physicochemical properties of drug and physiology of the gastrointestinal tract (GIT). Additionally, drug dissolution from its dosage form could constitute the slowest or rate-determining step in drug absorption [1] . The drug needs to leave the aqueous environment to interact with the membrane for permeation. Then the drug needs to survive metabolism and efflux by the intestine, liver and lung, the first-pass organs, before the drug reaches the systemic circulation [2]. These various events may lead to significant reduction of the orally administered dose. The intestine is an important tissue that regulates the extent of absorption of orally administered drugs, and the intestine, liver and lung are involved in first-pass removal [3,4]. The intestine is unique in that it is the anterior, portal tissue that regulates the flow of substrates to the liver, then the lung. The venous drainage of the intestine constitutes the majority of the blood supply to the liver, accounting for 75% of total liver blood flow. The drug concentration [5,6] and the intestinal flow rate [7], factors that alter the rate of drug delivery, affect the degree of saturability of the intestine as well as the liver. For drugs that are highly cleared by the intestine, the contribution of the liver or lung to drug metabolism will become reduced. By contrast, drugs that are poorly extracted by the intestine are able to reach the next first-pass organs, the liver and the lung, for removal [8,5,9]. This chapter describes the roles of intestinal transporters and metabolism in the determination of oral bioavailability and first-pass removal. The intestinal tissue is endowed with phase I and II enzymes, usually at lower levels compared to those for the liver. Drug metabolizing enzymes: UDP-glucuronosyltransferases (UGT), sulfotransferases (PST), and glutathione S-transferases (GST) exhibit a decreasing gradient along the intestinal wall, from duodenum to ileum [109-111,59] ( Table 2 ). The distribution of the human intestinal CYP3A4 paralleled that of the rat for the small intestine, and showed a slightly lower level at the duodenum before levels rise again at the jejunum, then finally decreasing towards the ileum [62,64,58,81]. 20 21 M.N. Martinez and G.L. Amidon. A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J. Clin. Pharmacol. 42:620-643 (2002). M. Gibaldi, R.N. Boyes and S. Feldman. The influence of first pass effect on availability of drugs. J. Pharm. Sci. 60:1338-1340 (1971). M. Rowland. The influence of route of administration on drug availability. J. Pharm. Sci. 101:70-74 (1972). X. Xu, H. Hirayama and K.S. Pang. First pass metabolism of salicylamide. Studies in the once through vascularly perfused rat intestine-liver preparation Drug Metab. Dispos. 17:556-563 (1989). H. Hirayama and K.S. Pang. First-pass metabolism of gentisamide: Influence of intestinal metabolism on hepatic formation of conjugates. Studies in the oncethrough vascularly perfused rat intestine-liver preparation. Drug Metab. Dispos. 18:580-578 (1990). J. Chen and K.S. Pang. Effect of flow on first-pass metabolism of drugs: single pass studies on 4-methylumbelliferone (4MU) conjugation in the serially perfused rat intestine and liver preparations. J. Pharmacol. Exp. Ther. 280:24-31 (1997). R. Gugler, P. Lain and D.L. Azarnoff. Effect of portacaval shunt on the disposition of drugs with and without first-pass effect.
doi:10.1007/b105246 fatcat:msitnbkd4zgs7k5tgj7tzo67pq