Volumes of distribution and mean residence time of drugs with linear tissue distribution and binding and nonlinear protein binding
 Haiyung Cheng,
 William R. Gillespie
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Based on a generalized model, equations for calculating the mean residence time in the body at single dose (MRT) and at steady state (MRT _{ss}), apparent steadystate volume of distribution ( \(\hat V_{ss}\) ) and steadystate volume of distribution (V _{ss}) are derived for a drug exhibiting nonlinear protein binding. Interrelationships between \(\hat V_{ss}\) andV _{ss} as well as betweenMRT andMRT _{ss} are also discussed and illustrated with simulated data. In addition, a method for estimating the central volume of distribution of the bound drug and the sum of the central volume of distribution of the unbound drug and the area under the first moment curve of distribution function for drugs with nonlinear protein binding is proposed and illustrated with both simulated and published data.
 Evans, G. H., Nies, A. S., Shand, D. G. (1973) The disposition of propranolol III. Decreased halflife and volume of distribution of a result of plasma binding in man, monkey, dog and rat. J. Pharmacol. Exp. Ther. 180: pp. 114122
 Yacobi, A., Levy, G. (1975) Comparative pharmacokinetics of coumarin anticoagulants XIV. Relationship between protein binding, distribution and elimination kinetics of warfarin in rats. J. Pharm. Sci. 64: pp. 16601664
 Gillette, J. R. (1971) Factors affecting drug metabolism. Ann. N.Y. Acad. Sci. 179: pp. 4366
 Wilkinson, G. R., Shand, D. G. (1975) A physiologic approach to hepatic drug clearance. Clin. Pharmacol. Ther. 18: pp. 377389
 Wagner, J. G. (1976) Simple model to explain effects of plasma protein binding and tissue binding on calculated volumes of distribution, apparent elimination rate constants and clearances. Eur. J. Clin. Pharmacol. 10: pp. 425432 CrossRef
 Øie, S., Tozer, T. N. (1979) Effect of altered plasma protein binding on apparent volume of distribution. J. Pharm. Sci. 68: pp. 12031205
 Jusko, W. J., Gretch, M. (1976) Plasma and tissue protein binding of drugs in pharmacokinetics. Drug. Metab. Rev. 5: pp. 43140
 Rocci, M. L., Jusko, W. J. (1981) Dosedependent protein binding and disposition of prednisolone in rabbits. J. Pharm. Sci. 70: pp. 12011204
 Jusko, W. J., Chiang, S. T. (1982) Distribution volume related to body weight and protein binding. J. Pharm. Sci. 71: pp. 469470
 McNamara, P. J., Gibaldi, M., Stoeckel, K. (1983) Volume of distribution terms for a drug (ceftriaxone) exhibiting concentrationdependent protein binding. I. Theoretical considerations. Eur. J. Clin. Pharmacol. 25: pp. 399405
 KrugerThiemer, E., Diller, W., Bunger, P. (1965) Pharmacokinetic models regarding protein binding of drugs. Antimicrob. Agents Chemother. 5: pp. 183191
 Martin, B. K. (1965) Kinetics of elimination of drugs possessing high affinity for the plasma protein. Nature 207: pp. 959960
 Coffey, J. J., Bullock, F. J., Schoenemann, P. T. (1971) Numerical solution of nonlinear pharmacokinetic equations: Effects of plasma protein binding on drug distribution and elimination. J. Pharm. Sci. 60: pp. 16231628
 McNamara, P. J., Levy, G., Gibaldi, M. (1979) Effect of plasma protein and tissue binding on the time course of drug concentration in plasma. J. Pharmacokin. Biopharm. 7: pp. 191206
 Wagner, J. G. (1971) Biopharmaceutics and Relevent Pharmacokinetics. Drug Intelligence Publications, Hamilton, IL
 Øie, S., Guentert, T. W., Tozer, T. N. (1980) Effect of saturable binding on the pharmacokinetics of drugs: A simulation. J. Pharm. Pharmacol. 32: pp. 471477
 Gillespie, W. R. (1993) Generalized pharmacokinetic modeling for drugs with nonlinear binding: I. Theoretical framework. J. Pharmacokin. Biopharm. 21: pp. 99124 CrossRef
 Gillespie, W. R., VengPedersen, P. (1985) Theorems and implications of a modelindependent elimination/distribution function decomposition of linear and some nonlinear drug dispositions. II. Clearance concepts applied to the evaluation of distribution kinetics. J. Pharmacokin. Biopharm. 13: pp. 441451
 Weiss, M. (1983) Residence time and accumulation of drugs in the body. Int. J. Clin. Pharmacol. Ther. Toxicol. 24: pp. 121126
 Oppenheimer, J. H., Schwartz, H. L., Surks, M. I. (1975) Determination of common parameters of iodothyronine metabolism and distribution in man by noncompartmental analysis. J. Clin. Endocrinol. Metab. 41: pp. 319324
 Benet, L. Z., Galeazzi, R. L. (1979) Noncompartmental determination of the steadystate volume of distribution. J. Pharm. Sci. 68: pp. 10711074
 Cheng, H., Jusko, W. J. (1988) Mean residence time concepts for pharmacokinetic systems with nonlinear drug elimination described by the MichaelisMenten equation. Pharm. Res. 5: pp. 156164
 Cheng, H., Gillespie, W. R., Jusko, W. J. (1994) Mean residence time concepts for nonlinear pharmacokinetic systems. Biopharm. Drug Dispos. 15: pp. 627641
 Rocci, M. L., Jusko, W. J. (1983) LAGRAN program for area and moments in pharmacokinetic analysis. Compt. Prog. Biomed. 16: pp. 203216
 McNamara, P. J., Gibaldi, M., Stoeckel, K. (1983) Volume of distribution terms for a drug (ceftriaxone) exhibiting concentrationdependent protein binding. II. Physiological significance. Eur. J. Clin. Pharmacol. 25: pp. 407412
 VengPedersen, P., Cheng, H., Jusko, W. J. (1991) Regarding doseindependent pharmacokinetic parameters in nonlinear pharmacokinetics. J. Pharm. Sci. 80: pp. 608612
 Title
 Volumes of distribution and mean residence time of drugs with linear tissue distribution and binding and nonlinear protein binding
 Journal

Journal of Pharmacokinetics and Biopharmaceutics
Volume 24, Issue 4 , pp 389402
 Cover Date
 19960801
 DOI
 10.1007/BF02353519
 Print ISSN
 0090466X
 Online ISSN
 15738744
 Publisher
 Kluwer Academic PublishersPlenum Publishers
 Additional Links
 Topics
 Keywords

 volumes of distribution
 mean residence time
 nonlinear protein binding
 Industry Sectors
 Authors

 Haiyung Cheng ^{(1)}
 William R. Gillespie ^{(3)}
 Author Affiliations

 1. Department of Drug Metabolism, Merck Research Laboratories, 19486, West Point, Pennsylvania
 3. Food and Drug Administration, 20857, Rockville, Maryland