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

Citation
N. Matsunaga et al., Application of the PKCYP-test to predict the amount of in vivo CYP2C11 using tolbutamide as a probe, BIOL PHAR B, 24(11), 2001, pp. 1305-1310
Citations number
23
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOLOGICAL & PHARMACEUTICAL BULLETIN
ISSN journal
0918-6158 → ACNP
Volume
24
Issue
11
Year of publication
2001
Pages
1305 - 1310
Database
ISI
SICI code
0918-6158(200111)24:11<1305:AOTPTP>2.0.ZU;2-F
Abstract
Previous reports have shown that the determination of drug metabolism capac ity can be made by the pharmacokinetic estimation of the quantity of cytoch rome P450 (CYP) in vivo (PKCYP-test), in which an apparent liver-to-blood f ree 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 i n vivo CYP2C11 by using tolbutamide as a probe, to confirm its validity usi ng a physiologically based pharmacokinetic rat model. Rats treated with carbon tetrachloride (CCl4-treated rats) were used as a m odel for low levels of CYP2C11 in the liver. In CCl4-treated rats, the tota l body clearance (CLtot) of tolbutamide and the amount of CYP2C11 fell to a bout a quarter and a third of that in control rats, respectively. The time- course of tolbutamide concentrations in serum in control rats could be simu lated by a physiologically-based pharmacokinetic model. In CCl4-treated rat s, take into consideration the qg value of control rats, the level of CYP2C 11 was accurately predicted by the PKCYP-test, and the time-course of tolbu tamide concentrations in serum could be predicted by the same physiological ly-based pharmacokinetic model. In conclusion, we have shown that the PKCYP-test can be used to predict lev els 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.