Application of the PKCYP-test to predict the amount of in vivo CYP2C11 using tolbutamide as a probe.
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 CYPIA2 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.
Matsunaga
N
N
Department of Pharmaceutics, Kyoritsu College of Pharmacy, Tokyo, Japan.
Nishijima
T
T
Hattori
K
K
Iizasa
H
H
Yamamoto
K
K
Kizu
J
J
Takanaka
A
A
Morikawa
A
A
Nakashima
E
E
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002251:Carbon Tetrachloride / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism* / Q000502:physiology; D000072467:Cytochrome P450 Family 2; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011237:Predictive Value of Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism* / Q000502:physiology; D013997:Time Factors; D014044:Tolbutamide / Q000097:blood / Q000493:pharmacokinetics*
D007004:Hypoglycemic Agents; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D002251:Carbon Tetrachloride; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase