Abstract
A novel approach for identifying the inter-individual variation in hepatic clearance was investigated based on physiological pharmacokinetic studies and estimations of the amount of cytochrome P450 (CYP)in vivo. This approach is referred to as the PKCYP-test. In order to correlate in vitro-in vivo metabolic parameters, we examined the apparent liver-to-blood free concentration gradient in vivo(qg). We confirmed the validity of the PKCYP-test using acetanilide and caffeine as the CYP1A2 probe and test drug, respectively, in rats.
Increased liver enzyme levels were induced in rats by the administration of 3-methylcholanthrene (MC) (MC-treated rats). We observed a 5-fold variation in the total body clearance (CLtot) of acetanilide, and a 10-fold variation in the CLtot of caffeine in control versus the MC-treated rats. Furthermore, the quantitation of CYP1A2 protein by Western blotting of liver microsomal protein, using a specific antibody, revealed a 20-fold increase in the MC-treated rats. The qg values were determined as the ratio of the in vivo-in vitro clearances. By considering the qg value of the control rats, we were able to predict the level of CYP1A2 in the MCtreated rats based on the CLtot, value of acetanilide. The CLtot values for caffeine in the MCtreated rats, as estimated from the predicted level of CYP1A2, closely correlated with the observed value.
In conclusion, we were able to show that it is possible to predict inter-individual differences in the metabolic clearance of patients with different amounts of CYP based on the specific qg value of a drug.
