M. Nakamura,1 S. Koh,2 A. Hisaka,3 H. Suzuki4; 1Chugai Pharmaceutical Co, Ltd., Tokyo, Japan, 2Asahi Kasei Pharma Corporation, Izunokuni, Japan, 3Chiba University, Chiba, Japan, 4University of Tokyo, Tokyo, Japan
BACKGROUND: Intestinal metabolism by CYP3A plays a role in lowering oral bioavailability of substrate drugs, and inhibition of the intestinal metabolism often causes noticeable drug-drug interactions (DDIs) on the contrary. Recently, we developed a new assessment method of intestinal availability (Fg) considering changes of AUC and plasma half-life (t1/2) in DDIs caused by strong inhibitors under an assumption of complete inhibition of the intestinal metabolism (Hisaka, Drug Metab Dispos, 2014;42:1640). In this study, we assessed the degree of inhibition of intestinal metabolism in addition to Fg simultaneously for broader DDI cases. At the same time, the developed analysis method can be considered as an extension of CR-IR method for systematic prediction of pharmacokinetic DDIs (Ohno, Clin Pharmacokin 2007;46:681), by separating hepatic and intestinal metabolic contributions.
METHODS: Based on clearance theory, changes in AUC and t1/2 in DDI were explained by four parameters, CRh (hepatic contribution ratio), IRh (hepatic inhibition ratio), Fg and IRg (IR in GI tracts). These four parameters were assessed simultaneously from AUC and t1/2 changes reported in the literature for 28 substrates and 13 inhibitors using the Gibbs sampling method with WinBUGS 1.4.
RESULTS: The present analysis indicated that IRh and IRg were similar except for grapefruit juice. Fg values calculated in this study agreed with those in the previous study. By using the new method, changes in t1/2 in addition to AUC can be predicted for various combinations of substrates and inhibitors of CYP3A from the four parameters.
CONCLUSION: A method was successfully developed to assess intestinal metabolism and the degree of inhibition, and also to predict changes in t1/2 and AUC in various DDIs caused by CYP3A inhibition.