Pharmaceutical excipients inhibit cytochrome P450 activity in cell free systems and after systemic administration

Excipients are largely used as inert vehicles in formulation. Recent studies indicated that some excipients could affect drug transport and disposition. But the effects of most excipients on drug metabolism are yet to be unveiled. To evaluate the actual action of pharmaceutical excipients in biotransformation, we examined the effects of 22 common excipients on cytochrome P450 3A4, the main CYP in intestinal and liver, using midazolam as the probe. The results showed that 15 of 22 (68.2%) tested excipients could inhibit the activity of CYP3A4 more than 50% in vitro, particularly the surfactants and polymers. To further understand these effects in vivo, five excipients were selected to study the effects on CYP3A4 in rats through the pharmacokinetics of midazolam and its primary metabolite 1′-hydroxymidazolam. In in vivo studies, most selected excipients significantly inhibited the activity of CYP3A4 by increasing the midazolam AUC0–∞ and decreasing the midazolam CL/F as well as decreasing the ratio of AUC0–∞ (1′-hydroxymidazolam)/AUC0–∞ (midazolam). For examples, single and multiple dose administration of PEG400 increased intraduodenally dosed midazolam AUC0–∞ to 1.78- and 1.51-fold, decreased midazolam CL/F from 8.86 to 5.25 and 6.28 L/h/kg and decreased the ratio of AUC0–∞ (1′-hydroxymidazolam)/AUC0–∞ (midazolam) from 1.14 to 0.34 and 0.39, respectively (p < 0.05). This study indicated that some excipients could change drug metabolism through the effects on cytochrome P450 activity, such as CYP3A4, and thus this kind of inhibition should be taken into consideration in drug formulation and administration.