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Effect of rifampin on enantioselective disposition and anti‐hypertensive effect of benidipine
Author(s) -
Sunwoo Yu Eun,
Nguyen Phuong Thi Thu,
Chien Chin May,
Ryu Ji Young,
Shon Jihong,
Shin JaeGook
Publication year - 2019
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13848
Subject(s) - cyp3a , pharmacology , crossover study , midazolam , amlodipine , oral administration , pharmacokinetics , dosing , medicine , blood pressure , chemistry , cytochrome p450 , metabolism , alternative medicine , pathology , sedation , placebo
Aims In 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. 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 ∞ 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)‐(−)‐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.