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 P450 (CYP) inhibition, specifically CYP3A inhibition, in expressed human CYP3A4, human liver microsomes, dog- and cynomolgus monkey intestinal microsomes. Results indicated a wide range of inhibition potentials and there appeared to be species differences with inhibition of CYP3A activity. Generally, greater inhibition of CYP3A activity was observed with amphiphilic ingredients (for example mixed micellar solutions, Tween 80, and oleic acid). From the data presented, it can be predicted that the majority of the ingredients tested would not have a significant impact on the potential inhibition, by the formulation, on any apparent first pass metabolism in the intestinal tract for new drug entities being tested in the preclinical environment. However a number of common ingredients will require further investigation based on the estimated concentration within the gastrointestinal tract.
Mountfield
R J
RJ
Drug Discovery Support, F. Hoffmann-La Roche, Pharmaceuticals Division, CH-4070, Basel, Switzerland. richard.mountfield@roche.com
Senepin
S
S
Schleimer
M
M
Walter
I
I
Bittner
B
B
D000818:Animals; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004064:Digestive System / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004285:Dogs; D006801:Humans; D020128:Inhibitory Concentration 50; D008252:Macaca fascicularis; D008823:Micelles; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009821:Oils / Q000494:pharmacology; D012997:Solvents / Q000494:pharmacology; D013045:Species Specificity; D013501:Surface-Active Agents / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D008823:Micelles; D009821:Oils; D012997:Solvents; D013501:Surface-Active Agents; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human