Application of the PKCYP-test to predict the amount of in vivo CYP2C11 using tolbutamide as a probe

Noriko Matsunaga, Taeko Nishijima, Kenji Hattori, Hisashi Iizasa, Keiko Yamamoto, Junko Kizu, Akira Takanaka, Akinobu Morikawa, Emi Nakashima

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Previous reports have shown that the determination of drug metabolism capacity can be made by the pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP-test), in which an apparent liver-to-blood free concentration gradient in vivo (qg) is introduced, which is useful for evaluating fluctuations of CYP1A2 in rats. The aim of the present study was to examine the application of the PKCYP-test to evaluate the quantity of in vivo CYP2C11 by using tolbutamide as a probe, to confirm its validity using a physiologically-based pharmacokinetic rat model. Rats treated with carbon tetrachloride (CCl4-treated rats) were used as a model for low levels of CYP2C11 in the liver. In CCl4-treated rats, the total body clearance (CLtot) of tolbutamide and the amount of CYP2C11 fell to about a quarter and a third of that in control rats, respectively. The time-course of tolbutamide concentrations in serum in control rats could be simulated by a physiologically-based pharmacokinetic model. In CCl4-treated rats, take into consideration the qg value of control rats, the level of CYP2C11 was accurately predicted by the PKCYP-test, and the time-course of tolbutamide concentrations in serum could be predicted by the same physiologically-based pharmacokinetic model. In conclusion, we have shown that the PKCYP-test can be used to predict levels of CYP2C11. It was also demonstrated that the qg and amount of CYP are useful parameters in the PKCYP-test by constructing a physiologically-based pharmacokinetic model which was applied to the PKCYP-test.

Original languageEnglish
Pages (from-to)1305-1310
Number of pages6
JournalBiological and Pharmaceutical Bulletin
Volume24
Issue number11
DOIs
Publication statusPublished - 2001 Nov 21

Keywords

  • CYP2C11
  • Carbon tetrachloride-treated
  • PKCYP-test
  • Physiologically-based pharmacokinetic model
  • Probe

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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    Matsunaga, N., Nishijima, T., Hattori, K., Iizasa, H., Yamamoto, K., Kizu, J., Takanaka, A., Morikawa, A., & Nakashima, E. (2001). Application of the PKCYP-test to predict the amount of in vivo CYP2C11 using tolbutamide as a probe. Biological and Pharmaceutical Bulletin, 24(11), 1305-1310. https://doi.org/10.1248/bpb.24.1305