Effect of polyoxyl ether analogous surfactants on the activity of cytochromes P450 3A in rats in vivo

To evaluate the effects of p-octyl polyethylene glycol phenyl ether (Triton X-100), polyoxyl 35 caster oil (EL35) and polyoxyl 40 hydrogenated caster oil (RH40) on the activity of Cytochrome P450 3A (CYP3As) in vivo. Rats were administered with saline, ketoconazole (75 mg·kg^-1·d^-1), Triton X-100 (30 mg·kg^-1·d^-1), EL35 (150 mg·kg^-1·d^-1) and RH40 (150 mg·kg^-1·d^-1) intragastrically for 5 consecutive days, and then given midazolam 10 mg·kg^-1 20 min after the last treatment of ketoconazole or three surfactants with the same dose through duodenal administration. Pharmacokinetics parameters for midazolam and its metabolite 1′-hydroxymidazolam were estimated from the plasma concentration-time data by a noncompartmental approach. The results showed that multiple dose administration of Triton X-100, EL35 and RH40 decreased the ratios of 1′-hydroxymidazolam and midazolam AUC_0-∞ from 1.14 to 0.90, 1.03 and 0.64, respectively. In contrast, multiple dose administration of ketoconazole caused the ratios of 1′-hydroxymidazolam and midazolam a significant decrease to 0.50. This study indicated that Triton X-100 and EL35 would have no inhibition on CYP3A, while RH40 had significant inhibition on CYP3A. Therefore, RH40 might be used to prepare drug formulations in pharmaceutical industry and would increase the bioavailability of some drugs transformed by CYP3As and further lead to significant clinical pharmacologic effects.