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Prediction of the disposition of nine weakly acidic and six weakly basic drugs in humans from pharmacokinetic parameters in rats

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Abstract

Various pharmacokinetic parameters—disposition half-life, t 1/2,z, metabolic clearance CLm, volume of distribution V, intrinsic clearance of unbound drug CLut, and unbound volume of distribution of tissues (distributive tissue volume / fraction of drug in tissue unbound, VT/fuT—are compared in rat and human for nine weakly acidic drugs, phenytoin, hexobarbital, pentobarbital, phenylbutazone, warfarin, tolbutamide, valproate, phenobarbital, and amobarbital, and six weakly basic drugs, quinidine, chlorpromazine, propranolol, pentazocin, antipyrine, and diazepam. With regard to all parameters, statistically significant correlations are obtained when parameters are plotted on a log-log plot. Correlation coefficients between the intrinsic parameters (CLuint or VT/fuT) were higher than those between the hybrid parameters (t1/2,z, CLm, or V). In general, these drugs were metabolized ten times more rapidly in rat than in human. With regard to the tissue distribution of these drugs, there was little difference between rat and human. Predictions of CLm, V, and t1/2, in humans using rat data were successful for most drugs, with a few marked exceptions.

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References

  1. L. B. Mellett. Comparative drug metabolism.Prog. Drug Res,13:136–169 (1969).

    CAS  PubMed  Google Scholar 

  2. R. L. Dedrick, K. B. Bischoff, and D. S. Zaharko. Interspecies correlation of plasma concentration history of methotrexate.Cancer Chemother. Part 1 54:95–101 (1970).

    CAS  Google Scholar 

  3. R. L. Dedrick. Animal scale up.J. Pharmacokin. Biopharm. 1:435–461 (1973).

    Article  CAS  Google Scholar 

  4. U. Klotz, K. H. Antonin, and P. R. Bieck. Pharmacokinetics and plasma binding of diazepam in man, dog, rabbit, guinea pig, and rat.J. Pharmacol. Exp. Ther. 199:67–73 (1976).

    CAS  PubMed  Google Scholar 

  5. C. H. Walker. Species differences in microsomal monoxygenase activity and their relationship to biological half-lives.Drug Metab. Rev. 7:295–323 (1978).

    Article  CAS  PubMed  Google Scholar 

  6. C. H. Walker. Species variations in some hepatic microsomal enzymes that metabolize xenobiotics. In: J. W. Bridges and L. F. Chasseaud (eds.),Progress in Drug Metabolism, Vol. 5, Wiley, London, 1980, Chapter 2, pp. 113–164.

    Google Scholar 

  7. R. L. Dedrick, D. D. Forester, J. N. Cannon, S. M. E. Dareen, and L. B. Mellett. Pharmacokinetics of 1-β-spd-arabino-furanosylcytosine (Ara-C) deamination in several species.Biochem. Pharmacol. 22:2405–2417 (1973).

    Article  CAS  PubMed  Google Scholar 

  8. H. Boxenbaum. Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance Extrapolation of data to benzodiazepines and phenytoin.J. Pharmacokin. Biopharm. 8:165–176 (1980).

    Article  CAS  Google Scholar 

  9. H. Boxenbaum. Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics.J. Pharmacokin. Biopharm. 10:201–227 (1982).

    Article  CAS  Google Scholar 

  10. H. Boxenbaum. Comparative pharmacokinetics of benzodiazepines in dog and man.J. Pharmacokin. Biopharm. 10:411–426 (1982).

    Article  CAS  Google Scholar 

  11. Y. Sawada, M. Hanano, Y. Sugiyama, and T. Iga. Prediction of the disposition ofβ-lactum antibiotics in human from pharmacokinetic parameters in animals.J. Pharmacokin. Biopharm. 12:241–261 (1984).

    Article  CAS  Google Scholar 

  12. L. Z. Benet and L. B. Sheiner. Design and optimization of dosage regimens; Pharmacokinetic data. In L. S. Goodman and A. Gilman (eds.),The Pharmacological Basis of Therapeutics, 6th ed. Macmillan, New York, 1980, pp. 699, 1737.

    Google Scholar 

  13. R. G. Dickison, R. C. Harland, A. M. Ilias, R. M. Rodgers, S. N. Kaufman, R. K. Lynn, and N. Gerber. Disposition of valproic acid in the rat: Dose-dependent metabolism, distribution, enterohepatic recirculation and choleretic effect.J. Pharmacol. Exp. Ther. 211:583–595 (1979).

    Google Scholar 

  14. Y. Tanimura. Pharmacokinetics of Phenylbutazone and Its Metabolites in Rats. Ph.D. thesis, University of Tokyo (1979).

  15. T. Inaba and T. Umeda. Biliary excretion of diphenylhydantoin in the rat.Drug Metab. Dispos. 3:69–73 (1975).

    CAS  PubMed  Google Scholar 

  16. T. Inaba, E. Tsutsumi, W. A. Mahon, and W. Kalow. Biliary excretion of diazepam in the rat.Drug Metab. Dispos. 2:429–432 (1974).

    CAS  PubMed  Google Scholar 

  17. F. Ichimura, K. Yokogawa, T. Yamana, A. Tsuji, and Y. Mizukami. Physiological pharmacokinetic model for pentazoxine. I. Tissue distribution and elimination in the rat.Int. J. Pharm. 15:321–333 (1983).

    Article  CAS  Google Scholar 

  18. K. S. Pang and M. Rowland. Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzyme activity on hepatic drug clearance.J. Pharmacokin. Biopharm. 5:625–653 (1977).

    Article  CAS  Google Scholar 

  19. G. R. Wilkinson and D. G. Shand. A physiological approach to hepatic drug clearance.Clin. Pharmacol. Ther. 18:377–390 (1975).

    CAS  PubMed  Google Scholar 

  20. O. Sugita, Y. Sawada, Y. Sugiyama, T. Iga, and M. Hanano. Effect of sulphaphenazole on tolbutamide distribution in rabbits. Analysis of interspecies difference in tissue distribution of tolbutamide.J. Pharm. Sci. 73:631–634 (1984).

    Article  CAS  PubMed  Google Scholar 

  21. J. W. Prothero. Scaling of blood parameters in mammals.Comp. Biochem. Physiol. 67A:649–657 (1980).

    Article  Google Scholar 

  22. U. K. Hansen. Molecular aspect of ligand binding to serum albumin.Pharmacol. Rev. 33: 17–53 (1981).

    Google Scholar 

  23. K. M. Piafsky. Disease-induced changes in the plasma binding of basic drugs.Clin. Pharmacokin. 5:246–262 (1980).

    Article  CAS  Google Scholar 

  24. M. K. Romach, K. M. Piafsky, J. G. Abel, V. Khouw, and E. M. Sellers. Methasone binding to orosomucoid (α 1-acid glycoprotein): Determinant of free fraction in plasma.Clin. Pharmacol. Ther. 29:211–217 (1981).

    Article  CAS  PubMed  Google Scholar 

  25. S. Glasson, R. Zili, P. D. Athis, J. P. Tillement, and J. R. Boissier. The distribution of bound propranolol between the different human serum proteins.Mol. Pharmacol. 17:187–191 (1980).

    CAS  PubMed  Google Scholar 

  26. W. E. Muller and A. E. Stillbaluer. Characterization of a common binding site for basic drugs on humanα 1-acid glycoprotein (orosomucoid).Naunyn-Schmiedeberg's Arch. Pharmacol. 322:170–173 (1983).

    Article  CAS  Google Scholar 

  27. J. J. Lima, H. Boudoulas, and M. Blanford. Concentration-dependence of disopyramide binding to plasma protein and its influence on kinetics and dynamics.J. Pharmacol. Exp. Ther. 219:741–747 (1981).

    CAS  PubMed  Google Scholar 

  28. O. G. Nilsin. Serum albumin and lipoproteins as the quinidine binding molecules in normal human sera. Biochem.Pharmacol. 25:1007–1012 (1976).

    Google Scholar 

  29. A. Yacobi and G. Levy. Comparative pharmacokinetics of coumarin and anticoagulants XIV: Relationship between protein binding distribution and elimination kinetics of warfarin in rats.J. Pharm. Sci. 64:1660–1664 (1975).

    Article  CAS  PubMed  Google Scholar 

  30. A. Yacobi, J. A. Udall, and G. Levy. Serum protein binding as a determinant of warfarin body clearance and anticoagulant effect.Clin. Pharmacol. Ther. 19:552–558 (1976).

    CAS  PubMed  Google Scholar 

  31. G. H. Evans, A. S. Nies, and D. G. Shand. The disposition of propanolol. III. Decreased half-life and volume of distribution as a result of plasma binding in man, monkey, dog and rat.J. Pharmacol. Exp. Ther. 186:114–122 (1973).

    CAS  PubMed  Google Scholar 

  32. D. Fremstad, O. G. Nilsen, L. Storstein, J. Amlie, and S. Jacobsen. Pharmacokinetics of quinidine related to plasma protein binding in man.Eur. J. Clin. Pharmacol. 15:187–192 (1979).

    Article  CAS  PubMed  Google Scholar 

  33. W. A. Colburn and M. Gibaldi. Plasma protein binding and metabolic clearance of phenytoin in the rat.J. Pharmacol. Exp. Ther. 203:500–506 (1977).

    CAS  PubMed  Google Scholar 

  34. Y. Igari, Y. Sugiyama, Y. Sawada, T. Iga, and M. Hanano. Prediction of diazepam disposition in the rat and man by a physiologically based pharmacokinetic model.J. Pharmacokin. Biopharm. 11: 577–593 (1983).

    Article  CAS  Google Scholar 

  35. H. Harashima, Y. Sawada, Y. Sugiyama, T. Iga, and M. Hanano. Analysis of non-linear tissue distribution of quinidine in rats by physiologically based pharmacokinetics.J. Pharmacokin. Biopharm. 13:425–440 (1985).

    Article  CAS  Google Scholar 

  36. T. Itoh, Y. Sawada, T. Iga, and M. Hanano. Unpublished data.

  37. Y. Igari, Y. Sugiyama, S. Awazu, and M. Hanano. Comparative physiologically based pharmacokinetics of hexobartital, phenobarbital and thiopental in the rat.J. Pharmacokin. Biopharm. 10:53–75 (1982).

    Article  CAS  Google Scholar 

  38. I. Odar-Cederloff and O. Borga. Kinetics of diphenylhydantoin in uremic patients: Consequences of decreased plasma protein binding.Eur. J. Clin. Pharmacol. 7:31–37 (1974).

    Article  Google Scholar 

  39. D. Kurata and G. R. Wilkinson. Erythrocyte uptake and plasma binding of diphenylhydantoin.Clin. Pharmacol. Ther. 16:355–362 (1974).

    CAS  PubMed  Google Scholar 

  40. D. D. Breimer, C. Honhoff, W. Zilly, E. Richter, and J. M. van Rossum. Pharmacokinetics of hexobarbital in man after intravenous infusion.J. Pharmacokin. Biopharm. 3:1–11 (1975).

    Article  CAS  Google Scholar 

  41. W. Zilly, D. D. Breimer, and E. Richter. Hexobarbital disposition in compensated and recompensated cirrhosis of the liver.Clin. Pharmacol. Ther. 23:525–534 (1978).

    CAS  PubMed  Google Scholar 

  42. Y. J. Lin, S. Awazu, M. Hanano, and H. Nogami. Pharmacokinetic aspects of elimination from plasma and distribution to brain and liver of barbiturates in rat.Chem. Pharm. Bull. (Tokyo) 21:2749–2756 (1973).

    Article  CAS  Google Scholar 

  43. M. Ernebo. Pharmacokinetics and distribution properties of pentobarbital in humans following oral and intravenous administration.J. Pharm. Sci. 63:1114–1118 (1974).

    Article  Google Scholar 

  44. M. Ehrnebo and I. Oder-Cederlof. Binding of amobarbital, pentobarbital and diphenylhydantoin to blood and plasma proteins in healthy volunteers and uraemic patients.Eur. J. Clin. Pharmacol. 8:445–453 (1975).

    Article  CAS  PubMed  Google Scholar 

  45. S. Toon and M. Rowland. Structure-pharmacokinetic relationships among the barbiturates in the rat.J. Pharmacol. Exp. Ther. 225:752–763 (1983).

    CAS  PubMed  Google Scholar 

  46. H. B. Hucker. Effect of halofenate on binding of various drugs to human plasma protein and on the plasma half life of antipyrine in monkeys.J. Pharm. Sci. 61:1490–1492 (1972).

    Article  CAS  PubMed  Google Scholar 

  47. J. T. Slattery, G. Levy, A. Jain, and F. G. McMahon. Effect of naproxen on the kinetics of elimination and anticoagulant activity of a single dose of warfarin.Clin. Pharmacol. Ther. 25:51–66 (1979).

    CAS  PubMed  Google Scholar 

  48. S. B. Matin, S. H. Wan, and J. H. Karam. Pharmacokinetics of tolbutamide: Prediction by concentration in saliva.Clin. Pharmacol. Ther. 16:1052–1057 (1974).

    CAS  PubMed  Google Scholar 

  49. O. Sugita, Y. Sawada, Y. Sugiyama, T. Iga, and M. Hanano. Prediction of drug-drug interaction fromin vitro plasma protein binding and metabolism: A study of tolbutamidesulfonamide interaction in rats.Biochem. Pharmacol. 30:3347–3354 (1981).

    Article  CAS  PubMed  Google Scholar 

  50. U. Klotz, T. Rapp, and W. A. Muller. Disposition of valproic acid in patients with liver disease.Eur. J. Clin. Pharmacol. 13:55–60 (1978).

    Article  CAS  PubMed  Google Scholar 

  51. W. Loscher. Serum protein binding and pharmacokinetics of valproate in man, dog, rat and mouse.J. Pharmacol. Exp. Ther. 204:255–261 (1978).

    CAS  PubMed  Google Scholar 

  52. A. J. Wilensky, P. N. Friel, R. H. Levy, C. P. Comfort and S. P. Kaluzny. Kinetics of phenobarbital in normal subjects and epileptic patients.Eur. J. Clin. Pharmacol. 23:87–92 (1982).

    Article  CAS  PubMed  Google Scholar 

  53. I. M. Patel, R. H. Levy, and R. E. Cutler. Phenobarbital-valproic acid interaction.Clin. Pharmacol. Ther. 27:32–36 (1980).

    Article  Google Scholar 

  54. J. N. Mcarther, P. D. Dawkins, and M. J. H. Smith. The binding of indomethacin, salicylate and phenobarbital to human whole bloodin vitro.J. Pharm. Pharmacol. 23:32–36 (1971).

    Article  Google Scholar 

  55. G. E. Mawer, N. E. Miller, and L. A. Turnberg. Metabolism of amylobarbitone in patients with chronic liver disease.Br. J. Pharmacol. 44:549–560 (1972).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. K. Balasubramaniam, S. B. Lucas, G. E. Mawer, and P. J. Simons. The kinetics of amylobarbitone metabolism in healthy men and women.Br. J. Pharmacol. 39:564–572 (1970).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. H. R. Oches, D. J. Greenblatt, E. Woo, K. Franke, and T. W. Smith. Effect of propranolol on pharmacokinetics and acute electrocardiographic changes following intravenous quinidine in humans.Pharmacology 17:301–306 (1978).

    Article  Google Scholar 

  58. I. E. Hughes, K. E. Ilett, and I. B. Jellett. The distribution of quinidine in human blood.Br. J. Clin. Pharmacol. 3:521–525 (1975).

    Article  Google Scholar 

  59. S. H. Curry. Relation between binding to plasma protein, apparent volume of distribution and rate constants of disposition and elimination for chlorpromazine in three species.J. Pharm. Pharmacol. 24:818–819 (1972).

    Article  CAS  PubMed  Google Scholar 

  60. M. H. Bickel. Binding of chlorpromazine and imipramine to red cells, albumin, lipoproteins and other blood components.J. Pharm. Pharmacol. 27:733–738 (1975).

    Article  CAS  PubMed  Google Scholar 

  61. M. Ehrnebo, S. Agurell, L. O. Boreus, E. Gordon, and U. Lonroth. Pentazocine binding to blood cells and plasma proteins.Clin. Pharmacol. Ther. 16:424–429 (1974).

    CAS  PubMed  Google Scholar 

  62. E. A. Neal, P. J. Meffin, P. B. Gregory, and T. F. Blaschke. Enhanced bioavailabilty and decreased clearance of analgesics in patients with cirrhosis.Gastroenterology 77:96–102 (1979).

    CAS  PubMed  Google Scholar 

  63. S. Agurell, L. O. Boreus, E. Gordon, J. E. Lindgrem, M. Ehrnebo, and U. Lonroth. Plasma and cerebrospinal fluid concentrations of pentazocine in patients: Assay by mass fragmentography.J. Pharm. Pharmacol. 26:1–8 (1974).

    Article  CAS  PubMed  Google Scholar 

  64. M. Ehrnebo, L. O. Boreus, and U. Lonroth. Bioavailability and first-pass metabolism of oral pentazocine in man.Clin. Pharmacol. Ther. 22:888–892 (1977).

    CAS  PubMed  Google Scholar 

  65. Y. Igari, Y. Sugiyama, Y. Sawada, T. Iga, and M. Hanano.In vitro andin vivo assessment of hepatic and extrahepatic metabolism of diazepam in the rat.J. Pharm. Sci. 73:825–828 (1984).

    Article  Google Scholar 

  66. T. Nakagawa, Y. Koyanagi, and H. Togawa. SALS, A Computer Program for Statistical Analysis with Least Squares Fitting. Library Program of University of Tokyo Computer Center, Tokyo, Japan (1978).

    Google Scholar 

  67. E. J. Triggs, R. L. Nation, A. Long, and J. J. Ashley. Pharmacokinetics in the elderly.Eur. J. Clin. Pharmacol. 8:55–62 (1975).

    Article  CAS  PubMed  Google Scholar 

  68. J. Aarbakke, O. M. Bakke, E. J. Milde, and D. S. Davies. Disposition and oxidation metabolism of phenylbutazone in man.Eur. J. Clin. Pharmacol. 11:359–366 (1977).

    Article  CAS  PubMed  Google Scholar 

  69. D. Horwitz, S. S. Thorgeirsson, and J. R. Mitchell. The influence of allopurinol and size of dose on the metabolism of phenylbutazone in patients with gout.Eur. J. Clin. Pharamcol. 12:133–136 (1977).

    Article  CAS  Google Scholar 

  70. P. J. Neuvonen and E. E. Elonen. Effect of activated charcoal on absorption and elimination of phenobarbital, carbamazepine and phenylbutazone in man.Eur. J. Clin. Pharmacol. 17:51–57 (1980).

    Article  CAS  PubMed  Google Scholar 

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  1. Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, 113, Tokyo, Japan

    Yasufumi Sawada, Manabu Hanano, Yuichi Sugiyama & Tatsuji Iga

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Sawada, Y., Hanano, M., Sugiyama, Y. et al. Prediction of the disposition of nine weakly acidic and six weakly basic drugs in humans from pharmacokinetic parameters in rats. Journal of Pharmacokinetics and Biopharmaceutics 13, 477–492 (1985). https://doi.org/10.1007/BF01059331

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