Enantioselective disposition of fexofenadine with the P-glycoprotein inhibitor verapamil.
OBJECTIVE
The aim was to compare possible effects of verapamil, as a P-glycoprotein (P-gp) inhibitor, on the pharmacokinetics of each fexofenadine enantiomer, as a P-gp substrate.


METHODS
Thirteen healthy Japanese volunteers (10 male and three female) were enrolled. In a randomized, two-phase, crossover design, verapamil was dosed 80 mg three times daily (with total daily doses of 240 mg) for 6 days, and on day 6, a single 120-mg dose of fexofenadine was administered along with an 80-mg dose of verapamil. Subsequently, fexofenadine was administered alone after a 2-week wash-out period. The plasma concentrations of fexofenadine enantiomers were measured up to 24 h after dosing.


RESULTS
During the control phase, the mean AUC(0-infinity) of S(-)- and R(+)-fexofenadine was 700 ng h(-1) ml(-1)[95% confidence interval (CI) 577, 823] and 1202 ng h(-1) ml(-1) (95% CI 1007, 1396), respectively, with a significant difference (P < 0.001). Verapamil had a greater effect on the pharmacokinetic parameters of S(-)-fexofenadine compared with those of the R(+)-enantiomer, and increased AUC(0-infinity) of S(-)-fexofenadine and R(+)-fexofenadine by 3.5-fold (95% CI of differences 1.9, 5.1; P < 0.001) and by 2.2-fold (95% CI of differences 1.7, 3.0; P < 0.001), respectively. The R/S ratio for the AUC(0-infinity) was reduced from 1.76 to 1.32 (P < 0.001) by verapamil treatments.


CONCLUSIONS
This study indicates that P-gp plays a key role in the stereoselectivity of fexofenadine pharmacokinetics, since the pharmacokinetics of fexofenadine enantiomers were altered by the P-gp inhibitor verapamil, and this effect was greater for S-fexofenadine compared with R-fexofenadine.
Sakugawa
Takashi
T
Department of Pharmacy, University of the Ryukyus, Okinawa, Japan.
Miura
Masatomo
M
Hokama
Nobuo
N
Suzuki
Toshio
T
Tateishi
Tomonori
T
Uno
Tsukasa
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology*; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016593:Terfenadine; D014700:Verapamil; C093230:fexofenadine