title: Application of the PKCYP test to predict caffeine clearance mediated by CYP1A2 in a rat acute liver injury model.
abstract: We previously established a method for assessing in vivo drug-metabolizing capacity by 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 (Matsunaga et al., Jpn. J. Hosp. Pharm., 26: 492-504 (2000)). This method was applied to estimate the amount of CYP2C11 in rats treated with carbon tetrachloride (CCl(4)-treated rats). In this study, we estimated the amount of CYP1A2 in CCl(4)-treated rats by using acetanilide and caffeine as a probe and a model drug, respectively. In CCl(4)-treated rats, the total body clearance (CL(tot)) of acetanilide and caffeine was about one-fifth and one-eighth of that in control rats, respectively. In CCl(4)-treated rats, the amount of CYP1A2 was predicted as 0.60+/-0.06 nmol/kg from the clearance of acetanilide mediated by CYP1A2. Moreover, the clearance of caffeine mediated by CYP1A2 in CCl(4)-treated rats was estimated as 0.47+/-0.05 mL/min/kg by using the predicted amount of CYP1A2. The observed value was 0.44+/-0.03 mL/min/kg, and the predicted value was within the 95% confidence interval of the observed value. In conclusion, we have demonstrated that the PKCYP test can also be applied for estimating the amount of CYP1A2 in CCl(4)-treated rats.
authors.affiliation: Department of Practical Pharmacy, Kyoritsu College of Pharmacy, Tokyo, Japan.
authors.forename: Noriko Kose
authors.initials: NK
authors.lastname: Matsunaga
authors.forename: Minae
authors.initials: M
authors.lastname: Isawa
authors.forename: Junko
authors.initials: J
authors.lastname: Kizu
authors.forename: Norio
authors.initials: N
authors.lastname: Miyazaki
authors.forename: Akira
authors.initials: A
authors.lastname: Takanaka
authors.forename: Emi
authors.initials: E
authors.lastname: Nakashima