Pharmacokinetics of fexofenadine enantiomers in healthy subjects.
Fexofenadine, a substrate of P-glycoprotein and an organic anion transporter polypeptide, is commonly used to assess P-glycoprotein activity in vivo. The purpose of this study was to elucidate the pharmacokinetics of each fexofenadine enantiomer. After a single oral dose of racemic fexofenadine (60 mg), the plasma and urine concentrations of fexofenadine enantiomers were measured over the course of 24 h in six healthy subjects. The mean plasma concentration of R(+)-fexofenadine was higher than that of S(-)-fexofenadine. The area under the plasma concentration-time curve (AUC(0-infinity)) and the maximum plasma concentration (C(max)) of R(+)-fexofenadine were significantly greater than those of the S(-)-enantiomer (P = 0.0018 and 0.0028, respectively). The R/S ratios of AUC and C(max) of fexofenadine were 1.75 and 1.63, respectively. The oral clearance and renal clearance of S(-)-fexofenadine were significantly greater than that of R(+)-fexofenadine (P = 0.0074 and 0.0036). On the other hand, the stereoselective metabolism of fexofenadine using recombinant CYP3A4 was investigated; however, fexofenadine enantiomers were not metabolized by CYP3A4. Fexofenadine is transported by both P-glycoprotein and OATP and is not metabolized by intestinal CYP3A. Our findings suggest that the affinity of P-glycoprotein for S(-)-fexofenadine is greater than its affinity for the R(+)-enantiomer. Thus, P-glycoprotein is likely to have chiral discriminatory abilities.
Miura
Masatomo
M
Department of Pharmacy, Akita University Hospital, Akita, Japan. m-miura@hos.akita-u.ac.jp
Uno
Tsukasa
T
Tateishi
Tomonori
T
Suzuki
Toshio
T
D000328:Adult; D005260:Female; D039563:Histamine H1 Antagonists, Non-Sedating / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D013237:Stereoisomerism; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D039563:Histamine H1 Antagonists, Non-Sedating; D016593:Terfenadine; C093230:fexofenadine