No abstract

Plasma XO activity correlates with indices of insulin resistance and liver dysfunction in Japanese patients with type 2 diabetes mellitus and MetS. Through assessing the plasma XO activity, patients showing normal levels of serum uric acid with higher activity of XO can be screened, thereby possibly providing a clue to uncovering metabolic risks in type 2 diabetes mellitus and MetS patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Recently, we have shown that itraconazole co-administration increases the plasma concentrations of S(-)-and R(+)-fexofenadine enantiomers, and it appears to affect this P-glycoprotein (P-gp)-mediated transport of S(-)-fexofenadine to a greater extent compared with that of R(+)-fexofenadine.• Although verapamil is a P-gp inhibitor and co-administration is known to increase the bioavailability of racemic fexofenadine, little is known about the inhibitory effect of verapamil for each fexofenadine enantiomer. WHAT THIS STUDY ADDS• Similar to the drug-interaction study with itraconazole, verapamil altered the stereoselective pharmacokinetics of fexofenadine to a greater extent on S(-)-fexofenadine than on R(+)-fexofenadine.• This effect by verapamil may be due to the differing affinities of P-gp for each enantiomer.• However, since the inhibitory effect of verapamil did not eliminate the difference in pharmacokinetics of fexofenadine enantiomers, it is likely that other mechanisms in addition to P-gp contribute to the stereoselective pharmacokinetics of fexofenadine. AIMSThe 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. METHODSThirteen 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. RESULTSDuring the control phase, the mean AUC0-• 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 AUC0-• 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 AUC0-• was reduced from 1.76 to 1.32 (P < 0.001) by verapamil treatments. CONCLUSIONThis 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.

In this study we examined the effect of the aqueous extract of Thonningia sanguinea (T.S.) on 7-ethoxyresorufin 0- deethylase (EROD, CYPlAl), 7-pentoxyresorufin-dealkylase (PROD, CYP2B1/2), 7-methoxyresorufin 0- demethylase (MROD, CYP1A2), aniline hydroxylase (aniline, CYP2E1), p-nitrophenol hydroxylase (PNPH, CYP2E1) and erythromycin N-demethylase (ERDM, CYP3A1) in rat liver in vitro and in vivo. Although T.S. extract increased ERDM activity in induced rat liver microsomes, it showed a dose-dependent inhibitory effectin vitro on other P450 monooxygenase activities particularly EROD and PROD, which are mediated primarily by CYPlAl and CYP2B1/2, respectively. PROD, EROD and MROD activities were also decreased by 18%, 19% and 40%, respectively, in hepatic microsomes prepared from rats treated with T.S. extract for 3 days. Kinetic analysis of CYP activity of 3-methylchloranthrene-induced microsomes demonstrated that T.S. inhibited EROD and MROD activities by a noncompetitive and competitive mechanism, respectively. The analysis of alterations produced by T.S. on PROD kinetic parameters in phenobarbital-induced microsomes suggested that the inhibition is noncompetitive. Pretreatment of rats with T.S. prolonged pentobarbital and phenobarbital sleeping time; however, plasma phenobarbital concentration determined on awakening showed no significant difference between control and T.S.-treated rats. T.S. was also found to be a potent inhibitor of the liver cytosolic glutathione S-transferase. These data suggest that selective modulation of CYP isoenzymes by T.S. might con-tribute to protection of the liver from xenobiotic-induced intoxication or to alteration of the action of drug (s) conco-mitantly administered besides its antioxidative properties.