2000 Volume 15 Issue 3 Pages 235-243
When the metabolism of a drug is competitively or noncompetitively inhibited by another drug, the degree of in vivo interaction can be evaluated from the Iu/Ki ratio, where Iu is the unbound concentration around the enzyme and Ki is the in vitro inhibition constant of the inhibitor. In the case of tolbutamide/sulfaphenazole interaction, the increase in tolbutamide AUC predicted using an estimated maximum value of Iu was comparable with the predictions taking the concentration profile of the inhibitor into consideration and also with the in vivo observation.
We have also evaluated the metabolic inhibition potential of a number of drugs known to be inhibitors or substrates of cytochrome P450 (CYP) by estimating their Iu/Ki ratio using literature data. Using the maximum unbound concentration of the inhibitor at the inlet to the liver as Iu, the possibility of drugs causing in vivo drug-drug interactions could be predicted based on their Iu/Ki ratios.
On the other hand, in the case of interactions involving a mechanism-based inhibition, it is necessary to consider the exposure time of the enzyme to the inhibitor and enzyme turnover in predicting from in vitro data. A case of 5-fluorouracil/sorivudine interaction has been predicted based on a physiologically-based pharmacokinetic model.
Although it can be assumed for most inhibitors that the value of Iu is equal to the unbound concentration in the liver capillary, this assumption is not valid if the inhibitor is actively taken up by the liver. In the in vitro uptake studies using isolated rat hepatocytes and ATP depletors, none of the investigated inhibitors was found to be highly concentrated in the liver, and the predicted in vivo interaction was not greatly affected by taking account of active transport of the inhibitor.
We have also attempted to establish a rational methodology for predicting the drug interactions via hepatic transporters responsible for drug uptake and subsequent excretion. Both isolated hepatocytes and canalicular membrane vesicles were used to determine the intrinsic potential for the interaction via hepatic uptake and biliary excretion at the sinusoidal and canalicular membranes, respectively. We have demonstrated that the degree of inhibition of each membrane transport process can be accurately estimated also by considering the Iu/Ki ratios. We have also established a rational methodology to predict the degree of inhibition of net biliary excretion (from blood to bile) which can also be applied to clinical situations and prevent researchers from making false negative predictions.
