Potential inhibitory effects of formulation ingredients on intestinal cytochrome P450

The use of common Formulation ingredients (categorized into six groups) for preclinical animal studies has been assessed with respect to cytochrome P4 50 (CYP) inhibition, specifically CYP3A inhibition, in expressed human CYP3 A4, human liver microsomes, dog- and cynomolgus monkey intestinal microsome s. Results indicated a wide range of inhibition potentials and there appear ed to be species differences with inhibition of CYP3A activity. Generally, greater inhibition of CYP3A activity was observed with amphiphilic ingredie nts (for example mixed micellar solutions, Tween 80, and oleic acid). From the data presented, it can be predicted that the majority of the ingredient s tested would not have a significant impact on the potential inhibition, b y the formulation, on any apparent first pass metabolism in the intestinal tract for new drug entities being tested in the preclinical environment. Ho wever a number of common ingredients will require further investigation bas ed on the estimated concentration within the gastrointestinal tract. (C) 20 00 Elsevier Science B.V. All rights reserved.