Original paper :AATEX 7(1):23-29,2000
The degree of in vivo drug-drug interactions caused by competitive or non- competitive inhibition of drug metabolism can be predicted using the in vitro inhibition constant (Ki) and the unbound concentration of inhibitor in the liver (Iu). Although it can be assumed for most inhibitors that the value of Iu is equal to the unbound concentration in the liver capillary (sinusoid) (Iout,u), Iu is larger than Iout,u if the inhibitor is actively taken up by the liver. In the present study, the possibility of active transport of inhibitors into the liver was evaluated using isolated rat hepatocytes. An uptake study using FCCP, an 4TP-depletor, showed that unbound quinidine, erythromycin, sulfaphenazole, ketoconazole, and omeprazole are concentrated 2.2-, 1.4-, 1.2-, 1.2-, and 1.0- fold. respectively, in hepatocytes due to active transport. This value of the unbound concentration ratio of each inhibitor was multiplied by the unbound concentration at the inlet to the liver (Iin,u) to estimate the maximum value of Iu, and the in vivo increase in the AUC of the corresponding substrates(sparteine, cyclosporine, tolbutamide, terfenadine, and diazepam, respectively) was predicted based on the Iu/Ki ratio. Because none of the investigated inhibitors was found to be highly concentrated in the liver, the predicted in vivo interaction was not greatly affected by taking account of active transport of the inhibitor.
Keywords: drug interaction, active transport, isolated rat hepatocyte