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

Abstract

AIMSIn vitro study showed that benidipine is exclusively metabolized by cytochrome P450 (CYP) 3A. This study evaluated the effect of rifampin on the enantioselective disposition and anti-hypertensive effect of benidipine. METHODSBenidipine (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)-(À)-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. RESULTSThe exposure of (S)-(S)-(+)-α-benidipine was greater than that of (R)-(R)-(À)-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 ∞ 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 ∞ for (R)-(R)-(À)-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. CONCLUSIONSAfter single administration of racemic benidipine, enantioselective disposition of (S)-(S)-(+)-αand (R)-(R)-(À)-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. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2019) 85 737-745 737• Benidipine is a racemic mixture of two isomers ((R)-(R)-(À)-α and (S)-(S)-(+)-α).• Our previous study indicated that benidipine was metabolized by CYP3A4 and CYP3A5.• Rifampin is a potent inducer of CYP3A4 that can decrease the antihypertensive effects of calcium channel blockers. WHAT THIS STUDY ADDS• A clinical study in healthy subjects was conducted to evaluate the enantioselective disposition of benidipine.• This study describes for the first time the effect of rifampin on the pharmacokinetic and pharmacodynamic properties of benidipine and its enantiomers to establish the mechanism of the drug interaction. Study design flow chart Effect of rifampin on benidipine PK/PD Br J Clin Pharmacol (2019) 85 737-745 739 Effect of rifampin on benidipine PK/PD Br J Clin Pharmacol (2019) 85 737-745 745

Assessing the Effect of the Anti-tuberculosis Drug Rifampicin on Known Hypertensive Patients With Tuberculosis in a Tertiary Care Center

“…It is the most influential enzyme inducer of hepatic cytochrome P450 enzymes that lead to increased metabolism of many drugs and turns them into ineffective drugs such as warfarin, birth control pills, antiretrovirals, immune suppressants, as well as some anti-hypertensives such as calcium channel blockers, beta-blockers, and diuretics [7]. Several studies have reported that rifampicin has potentially diminished the hypotensive effects of many anti-hypertensive agents by inducing cytochrome P450 [8][9][10]. Thus, this study aims to investigate the effect of rifampicin on the target blood pressure in known hypertensives whose blood pressure had been previously controlled with anti-hypertensives.…”