Application of the PKCYP Test to Predict Caffeine Clearance Mediated by CYP1A2 in a Rat Acute Liver Injury Model

Summary: We previously established a method for assessing in vivo drug­metabolizing capacity by pharmacokinetic estimation of the quantity of cytochrome P450 (CYP) in vivo (PKCYP test), in which an apparent liver­to­blood 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 one­fifth and one­eighth 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.