Summary
Since drug candidates with low oral systemic exposure may be due to either or both absorption and metabolism factors, determining what factors limit the oral systemic exposure is not always obvious in a singlein-vivo pharmacokinetic (PK) assay. A rapid ratin-vivo PK screen where the oxidative drug metabolism has been attenuated using the suicide CYP450 inhibitor aminobenzotriazole (ABT) is described. We have shown that the roles of absorption and metabolism for drug candidates with low oral systemic exposure can be determined by comparing the PK parameters of drug candidates orally administered to non-treated and ABT-treated rats. Propranolol, metoprolol and climetidine are used as model drugs. Propranolol and metoprolol have low oral systemic exposures in rats primarily due to metabolism factors while the oral systemic exposure of climetidine is high in rats. For propranolol and metoprolol, large increases in the systemic exposure of these drugs were observed between non-treated and ABT-treated rats. ABT appeared not to increase or decrease significantly the rate and extent of absorption or metabolism of Cimetidine since that oral systemic exposure of non-treated and ABT-treated rats did not significantly change.
These experiments suggest that for drug candidates with low systemic exposures in rats an observation of no change in the oral systemic exposure in ABT-treated rats when compared to the non-treated rats imply that absorption (or formulation) factors limit the systemic exposure of the drug while an increase in the systemic exposure in ABT-treated rats imply that metabolism factors limit the systemic exposure. Due to the ease of preparing and interpreting PK data from ABT-treated rats, is suggested that this assay could be used as an alternative toin vivo cannulation assays. Please send reprint requests to: Dr G. W. Caldwell,
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References
Caldwell, G. W. (2000). Compound optimization in early- and late-phase drug discovery: acceptable pharmacokinetic properties utilizing combined physicochemical, in vitro and in vivo screens. [Published erratum appears in Curr Opin in Drug Discov Develop 2000, 3(2), 250]. Curr Opin in Drug Discov Devel 3(1), 30–41.
Caldwell, G. W.; Ritchie, D. M.; Masucci, J. A.; Hageman, W. (2001). The new pre-preclinical paradigm: compound optimization in early and late phase drug discovery. Curr Top in Med Chem 1(5), 353–366.
Caldwell, G. W.; Yan, Z.; Masucci, J. A.; Hageman, W.; Ritchie, D. M. (2003). Applied Pharmacokinetics in Drug Development. An Overview of Drug Discovery. Pharm Dev Regul 1(2), 117- 132.
Cox, K. A.; Dunn-Meynell, K.; Korfmacher, W. A.; Broske, L.; Nomeir, A. A.; Lin, C.-C; Cayen, M. N.; Barr, W. H. (1999). Novel in vivo procedure for rapid pharmacokinetic screening of discovery compounds in rats. Drug Discovery Today 4(5), 232–237.
Watt A.P., Morrison D., Evans D.C. (2000). Approaches to higher-through pharmacokinetics (HTPK) in drug discovery. Drug discovery Today 5(1), 17–24.
White R.E. (2000). High-through screening in drug metabolism and pharmacokinetics support of drug discovery. Annu Rev Pharmacol Toxicol 40, 133–157.
Masucci, John A.; Caldwell, Gary W.; Jones, William J.; Juzwin, Stephen J.; Sasso, Patrick J.; Evangelisto, Mary. (2001). The use of on-line and off-line chromatographic extraction techniques coupled with mass spectrometry for support of in vivo and in vitro assays in drug discovery. Cur. Topics in Med Chem 1(5), 463–471.
Chiou, W.L.; Robbie, G.; Chung, S.M.; Wu, T-C; Ma, C. (1998). Correlation of plasma clearance of 54 extensively metabolized drugs between humans and rats: mean allometric coefficient of 0.66. Pharm Res 15(9), 1474–1479.
Bachmann, K.; Pardoe, D.; White, D. (1996). Scaling basic toxicokinetic parameters from rat to human. Environ health Perspect 10494), 400–407
Mahmood, I. (2000). Can absolute oral bioavailability in humans be predicted from animals? A comparison of allometry and different indirect methods. Drug Metab Drug Int 16(2), 143–155
Caldwell, G.W.; Masucci, J.A.; Yan, Z.; Hageman, W. (2004). Allometric scaling of pharmacokinetic parameters in drug discovery: Can human CL, Vssand t1/2 be predicted from in-vivo rat data? Eur J Drug Metab Pharm 29(2), 133–143.
Ortiz de Montellano, Paul R.; Mico, Bruce A.; Mathews, James M.; Kunze, Kent L.; Miwa, Gerald T.; Lu, Anthony Y. H. (1981). Selective inactivation of cytochrome P-450 isozymes by suicide substrates. Archives of Biochemistry and Biophysics 210(2), 717–28.
Balani, Suresh K.; Zhu, Tong; Yang, Tian J.; Liu, Zhi; He, Bing; Lee, Frank W. (2002). Effective dosing regimen of 1-aminobenzotriazole for inhibition of antipyrine clearance in rats, dogs, and monkeys. Drug Metabolism and Disposition 30(10), 1059–1062.
Mugford, Cheryl A.; Mortillo, Mildred; Mico, Bruce A.; Tarloff, Joan B. (1992). 1-Aminobenzotriazole-induced destruction of hepatic and renal cytochromes P450 in male Sprague-Dawley rats. Fundamental and Applied Toxicology 19(1), 43–9.
Soltis, Michael; Colby, Howard D. (1998). Inhibition of testicular steroid metabolism by administration of 1-aminobenzotriazole to rats. Pharmacology 56(1), 51–56.
Meschter, C. L.; Mico, B. A.; Mortillo, M.; Feldman, D.; Garland, W. A.; Riley, J. A.; Kaufman, L. S. (1994). A 13-week toxicologic and pathologic evaluation of prolonged cytochromes P450 inhibition by 1-aminobenzotriazole in male rats. Fundamental and Applied Toxicology 22(3), 369–81.
Town, C.; Henderson, L.; Chang, D.; Mortillo, M.; Garland, W. (1993). Distribution of 1-aminobenzotriazole in male rats after administration of an oral dose. Xenobiotica, 23(4), 383–90.
Colby, Howard D.; Abbott, Brian; Cachovic, Michael; Debolt, Kristine M.; Mico, Bruce A. (1995). Inactivation of adrenal cytochromes P450 by 1-aminobenzotriazole. Biochemical Pharmacology 49(8), 1057–62.
Mico, Bruce A.; Federowicz, Debra A.; Ripple, Mary G.; Kerns, William. (1988). In vivo inhibition of oxidative drug metabolism by, and acute toxicity of, 1-aminobenzotriazole (ABT). A tool for biochemical toxicology. Biochemical Pharmacology 37(13), 2515–19.
Mico, Bruce A.; Federowicz, Debra Ann; Burak, Eric; Swagzdis, James E. (1987). In vivo inhibition of phenacetin oxidation by suicide substrate 1 -aminobenzotriazole. Drug Metabolism and Disposition 15(2), 274–6.
Mugford, Cheryl A.; Tarloff, Joan B. (1997). The contribution of oxidation and deacetylation to acetaminophen nephrotoxicity in female Sprague-Dawley rats. Toxicology Letters 93(1), 15–22.
Henesey, Caroline M.; Harvison, Peter J. (2002). Renal damage, metabolism and covalent binding following administration of the nephrotoxicant N-(3, 5-dichlorophenyl)succinimide (NDPS) to male Fischer 344 rats. Toxicology 170(3), 187–200.
Shargel, L.; Yu, A.B.C. (1993). Applied Biopharmaceutical and Pharmacokinetics, 3rd Edition, Appleton and Lange, Stamford, CT.
Miller, J.C.; Miller, J.N. (1992). Statistics for analytical chemistry, 2nd Edition, Ellis Hardwood Limited, West Sussex, England.
Belpaire, F. M.; Smet, F. DE.; Vynckier, L. J.; Vermeiden, A. M.; Rosseel, M. T.; Bogaert, M. G.; Chauvelot-Moachon, L. (1990). Effect of aging on the pharmacokinetics of atenolol, metoprolol and propranolol in the rat. J Pharmacol Exp Therapeutics 254(1), 116–122.
Shibasaki, S.; Asahina, M.; Kawamata, Y.; Kojo, M.; Nishigaki, R.; Umemura, K. (1989). The inhibitor effects of Cimetidine on elimination and distribution of propranolol in rats. J. Pharmacobio-Dyn 12, 549–557.
Weiner, I.M.; Roth, L. ( 1981 ). Renal excretion of Cimetidine. J Pharmacol Exp Therapeutics 216(3), 516–520.
Knodell, R.G.; Browne, D.; Gwodz, G.P.; Brian, W.R.; Guengerich, F.P. (1991). Differential inhibition of human liver cytochrome P-450 by Cimetidine, Gastroenterology 101, 1680–1691.
Griffiths, R.; Lewis, A.; Jeffrey, P. (1996). Models of drug absorption in situ and in conscious animals. Chapter 5 in Models for Assessing Drug Absorption and Metabolism, Eds. Borchardt, Smith and Wilson, Plenum Press, New York, page 67–82.
Akrawi, S.H.; Wedlung, P.J. (1987). Method for chronic portal vein infusion in unrestrained rats. J Pharmacol Methods 17(1), 67–74.
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Caldwell, G.W., Ritchie, D.M., Masucci, J.A. et al. The use of the suicide CYP450 inhibitor ABT for distinguishing absorption and metabolism processes in in-vivo pharmacokinetic screens. Eur. J. Drug Metab. Pharmacokinet. 30, 75–83 (2005). https://doi.org/10.1007/BF03226411
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DOI: https://doi.org/10.1007/BF03226411