Effect of rifampin on enantioselective disposition and anti‐hypertensive effect of benidipine

Aims

In vitro study showed that benidipine is exclusively metabolised by cytochrome P450 (CYP) 3A. This study evaluated the effect of rifampin on the enantioselective disposition and anti‐hypertensive effect of benidipine.

Methods

Benidipine (8 mg) was administered to healthy subjects with or without repeated rifampin dosing, in a crossover design. Plasma concentrations of (S)‐(S)‐(+)‐α and (R)‐(R)‐(−)‐α isomers of benidipine and blood pressure were measured for up to 24 h after dosing. In addition, CYP3A metabolic capacity was evaluated in each subject using oral clearance of midazolam.

Results

The exposure of (S)‐(S)‐(+)‐α‐benidipine was greater than that of (R)‐(R)‐(−)‐α‐benidipine by approximately three‐fold following single dose of benidipine. Repeated doses of rifampin significantly decreased the exposure of both isomers. Geometric mean ratios (GMRs) (95% CI) of C_max and AUC_inf for (S)‐(S)‐(+)‐α‐benidipine were 0.14 (0.10–0.18) and 0.12 (0.08–0.18), respectively. GMRs (95% CI) of C_max and AUC_inf for (R)‐(R)‐(−)‐α‐benidipine were 0.10 (0.06–0.17) and 0.10 (0.06–0.17), respectively. Oral clearances of both isomers were increased equally by approximately 10‐fold. There were no significant differences in cardiovascular effect following benidipine administration between control and rifampin treatment. CYP3A activity using midazolam did not appear to correlate with oral clearance of benidipine.

Conclusions

After single administration of racemic benidipine, enantioselective disposition of (S)‐(S)‐(+)‐α‐ and (R)‐(R)‐(−)‐α‐benidipine was observed. Treatments with rifampin significantly decreased the exposure of both isomers but appeared to marginally affect its blood pressure‐lowering effect in healthy subjects. Impact of coadministration of rifampin on the treatment effects of benidipine should be assessed in hypertensive patients.

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