Effects of breviscapine and C3435T MDR1 gene polymorphism on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy volunteers

Breviscapine (BRE) is usually used for long-term use in patients with cardiovascular diseases such as coronary heart disease, angina pectoris, and cerebral thrombosis. It is possible to combine it with P-glycoprotein (P-gp) substrates in clinic. At present, little is known about whether the simultaneous use of BRE affects the disposal of P-gp substrates. The aim of this study was to evaluate the effect of BRE on the pharmacokinetics of fexofenadine (FEX), a P-gp probe substrate and its associations with the MDR1 C3435T genetic polymorphism in healthy volunteers. In this randomised, open-label, placebo-controlled, two-phase crossover clinical study, drug interactions were evaluated in healthy volunteers. FEX was used as a phenotypic probe for P-gp. In each phase, 18 volunteers were given daily doses of 120 mg (40 mg, three times a day) of BRE tablet or a placebo for 14 days. On day 15, a single oral dose of 120 mg FEX hydrochloride was given orally. Blood samples were collected at predefined time intervals, and plasma levels of FEX were determined by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The pharmacokinetic parameters were calculated by non-compartmental method, and bioequivalence was evaluated. Results showed that BRE pretreatment did not significantly affect the pharmacokinetics of FEX. The peak maximum plasma concentration (C (max)) and the area under the plasma concentration-time curve from zero to infinity (AUC(inf)) mean value of FEX with BRE and placebo-treated groups were 699 ng/mL vs. 710 ng/mL and 2972.5 ng.h/mL vs. 3460.5 ng.h/mL, respectively. The geometric mean ratios (90% confidence intervals) for FEX C (max) and AUC(inf) were within the pre-specified range of 0.8-1.25, indicating that FEX in the two pretreatment phases were bioequivalent. Pharmacokinetic parameters of FEX showed no statistically significant difference between MDR1 C3435T CC, CT and TT genotype, revealing that BRE and MDR1 C3435T gene polymorphisms did not affect the pharmacokinetics of FEX in healthy volunteers.