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.