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Aims We determined whether or not the extent of drug interaction of fexofenadine by itraconazole is time-dependent. Methods In a randomized two-phase crossover study, itraconazole was administered orally for 6 days, and, on days 1, 3 and 6, fexofenadine was administered simultaneously. On another occasion, fexofenadine was administered alone. Results Itraconazole increased fexofenadine AUC(0, ∞), and the % change for difference was 178% (95% CI 1235, 3379), 205% (95% CI 1539, 3319) and 169% (95% CI 1128, 2987) on days 1, 3 and 6 of the 6 day treatment, respectively. Conclusions The extent of drug interaction by itraconazole was not time-dependent. [ABSTRACT FROM AUTHOR]

Aim To examine the effect of grapefruit juice, an inhibitor of CYP3A4 in the small intestine, on the disposition of manidipine enantiomers in healthy subjects. Methods A randomized cross-over study with at least a 2-week wash-out period was performed. Seven healthy male volunteers received an oral 40-mg dose of racemic manidipine after an overnight fast with either grapefruit juice (GFJ) or water, as a control study. Plasma concentrations of (S)- and (R)-manidipine were monitored up to 10 h after the dosing. Results The plasma concentrations of (S)-manidipine were significantly higher ( P < 0.001) than those of (R)-manidipine in the control phase with an S/R ratio for the AUC0–∞ of 1.62 (95% confidence interval 1.52, 1.73). GFJ significantly increased Cmax and AUC0–∞ of (S)-manidipine by 2.4-fold ( P < 0.01) and 2.3-fold ( P < 0.01), respectively, and Cmax and AUC0–∞ of (R)-manidipine were increased by 3.4-fold ( P < 0.01) and 3.0-fold ( P < 0.01), respectively. There were significant differences ( P < 0.01) in GFJ-mediated percentage increases in Cmax and AUC0–∞ of (S)-manidipine compared with those of (R)-manidipine. The S/R ratio for AUC0–∞ was significantly decreased from 1.6 to 1.2 during the GFJ phase ( P < 0.01). Conclusion These results indicate that the stereoselective disposition of manidipine was altered by GFJ, as an inhibitor of CYP3A4. GFJ appears to affect this metabolic disposal of (R)-manidipine to a greater extent than that of (S)-manidipine. [ABSTRACT FROM AUTHOR]

Aims Fexofenadine is a substrate of several drug transporters including P-glycoprotein. Our objective was to evaluate the possible effects of two P-glycoprotein inhibitors, itraconazole and diltiazem, on the pharmacokinetics of fexofenadine, a putative probe of P-glycoprotein activity in vivo, and compare the inhibitory effect between the two in healthy volunteers. Methods In a randomized three-phase crossover study, eight healthy volunteers were given oral doses of 100 mg itraconazole twice daily, 100 mg diltiazem twice daily or a placebo capsule twice daily (control) for 5 days. On the morning of day 5 each subject was given 120 mg fexofenadine, and plasma concentrations and urinary excretion of fexofenadine were measured up to 48 h after dosing. Results Itraconazole pretreatment significantly increased mean (± SD) peak plasma concentration ( Cmax) of fexofenadine from 699 (± 366) ng ml−1 to 1346 (± 561) ng ml−1 (95% CI of differences 253, 1040; P < 0.005) and the area under the plasma concentration-time curve [AUC(0,∞)] from 4133 (± 1776) ng ml−1 h to 11287 (± 4552) ng ml−1 h (95% CI 3731, 10575; P < 0.0001). Elimination half-life and renal clearance in the itraconazole phase were not altered significantly compared with those in the control phase. In contrast, diltiazem pretreatment did not affect Cmax (704 ± 316 ng ml−1, 95% CI −145, 155), AUC(0, ∞) (4433 ± 1565 ng ml−1 h, 95% CI −1353, 754), or other pharmacokinetic parameters of fexofenadine. Conclusions Although some drug transporters other than P-glycoprotein are thought to play an important role in fexofenadine pharmacokinetics, itraconazole pretreatment increased fexofenadine exposure, probably due to the reduced first-pass effect by inhibiting the P-glycoprotein activity. As diltiazem pretreatment did not alter fexofenadine pharmacokinetics, therapeutic doses of diltiazem are unlikely to affect the P-glycoprotein activity in vivo. [ABSTRACT FROM AUTHOR]

Aims Rabeprazole is known to be a substrate of CYP2C19. Our objective was to evaluate the possible effect of an inhibitor of CYP2C19, fluvoxamine, and compare the inhibitory effect of fluvoxamine on the metabolism of rabeprazole between CYP2C19 genotypes. Methods A two-way randomized double-blind, placebo-controlled crossover study was performed. Twenty-one volunteers, of whom seven were homozygous extensive metabolizers (EMs), eight were heterozygous EMs and six were poor metabolizers (PMs) for CYP2C19, received two 6-day courses of either fluvoxamine 50 mg or placebo daily in a randomized fashion with a single oral dose of rabeprazole 20 mg on day 6 in all cases. Plasma concentrations of rabeprazole and its metabolite rabeprazole thioether were monitored up to 24 h after dosing. Results During placebo administration, the mean AUCs(0,∞) of rabeprazole in homozygous EMs, heterozygous EMs and PMs were 882 (95% CI, 602, 1162) ng ml−1h , 1214 (975, 1453) ng ml−1 h and 2762 (2482, 3042) ng ml−1 h ( P < 0.001), respectively. Fluvoxamine treatment increased AUC(0,∞) of rabeprazole and rabeprazole thioether by 2.8-fold ( P < 0.001) and 5.1-fold ( P < 0.01) in homozygous EMs, and by 1.7-fold ( P < 0.01) and 2.6-fold ( P < 0.01) in heterozygous EMs, and significantly prolonged the elimination half-life of rabeprazole and rabeprazole thioether in homozygous EMs and in heterozygous EMs, whereas no difference in any pharmacokinetic parameters was found in PMs. There was a significant difference in fluvoxamine-mediated percentage increase in AUC(0,∞) of rabeprazole and rabeprazole thioether between CYP2C19 genotypes. Conclusions The present study indicates that there are significant drug interactions between rabeprazole and fluvoxamine in EMs of CYP2C19. It is predominantly involved in rabeprazole and rabeprazole thioether metabolism in EMs. Therefore, CYP2C19 is the key determinant of rabeprazole disposition in EMs. [ABSTRACT FROM AUTHOR]

Lansoprazole is affected by polymorphism of CYP2C19. The aim of this study was to examine the effects of fluvoxamine, a CYP2C19 inhibitor, on the pharmacokinetics of each lansoprazole enantiomer among three different CYP2C19 genotype groups. Eighteen healthy subjects, of whom six each were homozygous extensive metabolizers (homEMs), heterozygous extensive metabolizers (hetEMs), or poor metabolizers (PMs) for CYP2C19, participated in the study. Each subject received either placebo or fluvoxamine, 25 mg twice daily for 6 days, then a single oral dose of 60 mg of racemic lansoprazole. The plasma concentrations of lansoprazole enantiomers and lansoprazole sulphone were subsequently measured for 24 h post lansoprazole administration using liquid chromatography. In the homEMs and hetEMs, fluvoxamine significantly increased the AUC(0, ∞) and Cmax and prolonged the elimination half-life of both (R)- and (S)-lansoprazole, whereas in the PMs, the only statistically significant effect of fluvoxamine was on the AUC(0, ∞) for (R)-lansoprazole. The mean fluvoxamine-mediated percent increase in the AUC(0, ∞) of (R)-lansoprazole in the homEMs compared with the PMs was significant ( P = 0.0117); however, Cmax did not differ among the three CYP2C19 genotypes. On the other hand, fluvoxamine induced a significant percent increase in both the AUC(0, ∞) and Cmax for (S)-lansoprazole in the homEMs compared with the hetEMs ( P = 0.0007 and P = 0.0125, respectively) as well as compared with the PMs ( P < 0.0001 for each parameter). The mean R : S ratio for AUC(0, ∞) of lansoprazole in the homEMs was significantly different between the placebo and the fluvoxamine treatment groups (12.7 (9.1, 16.8) vs 6.4 (5.4, 7.4), respectively, P < 0.0001), though not in the PMs (5.5 (4.3, 6.7) vs 5.9 (5.3, 6.5), respectively). The magnitude of the contribution of CYP2C19 to the metabolism of (S)-lansoprazole is much greater compared with that of the (R)-enantiomer. In extensive metabolizers, hepatic CYP2C19 plays an important role in the absorption and elimination of lansoprazole, particularly the (S)-enantiomer. [ABSTRACT FROM AUTHOR]

Lansoprazole is a substrate of CYP2C19 and CYP3A. The aim of this study was to compare the inhibitory effects of clarithromycin, an inhibitor of CYP3A on the metabolism of lansoprazole betweenCYP2C19genotypes.A two-way randomized double-blind, placebo-controlled crossover study was performed. Eighteen volunteers, of whom six were homozygous extensive metabolizers (EMs), six were heterozygous EMs and six were poor metabolizers (PMs) for CYP2C19, received two 6-day courses of either clarithromycin 800 mg or placebo daily in a randomized fashion with a single oral dose of lansoprazole 60 mg on day 6 in all cases. Plasma concentrations of lansoprazole and its metabolites, 5-hydroxylansoprazole and lansoprazole sulphone were monitored up to 24 h after dosing.During placebo administration, the mean AUC(0,∞) of lansoprazole in homozygous EMs, heterozygous EMs and PMs were 4652 (95% CI, 2294, 7009) ng ml−1 h, 8299 (4784, 11814) ng ml−1 h and 25293 (17643, 32943) ng ml−1 h (P < 0.001), respectively. Clarithromycin treatment significantly increasedCmax by 1.47-fold, 1.71-fold and 1.52-fold and AUC(0,∞) of lansoprazole by 1.55-fold, 1.74-fold, and 1.80-fold in these genotype groups, respectively, whereas elimination half-life was prolonged only in PMs. The clarithromycin-mediated percent increase in pharmacokinetic parameters such asCmax, AUC(0,∞) or elimination half-life did not differ between the threeCYP2C19genotypes.The present study indicates that there are significant drug interactions between lansoprazole and clarithromycin in allCYP2C19genotype groups probably through CYP3A inhibition. The bioavailability of lansoprazole might, to some extent, be increased through inhibition of P-glycoprotein during clarithromycin treatment. [ABSTRACT FROM AUTHOR]

Objective: Fexofenadine is a substrate of P-glycoprotein and organic anion transporting polypeptides. The aim of this study was to compare the inhibitory effects of different transporting inhibitors on fexofenadine pharmacokinetics. Methods: Twelve male volunteers took a single oral 120-mg dose of fexofenadine. Thereafter three 6-day courses of either 240 mg verapamil, an inhibitor of P-glycoprotein, 800 mg cimetidine, an inhibitor of organic cation transporters, or 2000 mg probenecid, an inhibitor of organic anion transporting polypeptides, were administered on a daily basis in a randomized fashion with the same dose of fexofenadine on day 6. Plasma and urine concentrations of fexofenadine were monitored up to 48 hours after dosing. Results: Verapamil treatment significantly increased the peak plasma concentration by 2.9-fold (95% confidence interval [CI], 2.4- to 4.0-fold) and the area under the plasma concentration-time curve from time 0 to infinity [AUC(0-∞)] of fexofenadine by 2.5-fold (95% CI, 2.0- to 3.3-fold). No changes in any plasma pharmacokinetic parameters of fexofenadine were found during cimetidine treatment. AUC(0-∞) was slightly but significantly increased during probenecid treatment by 1.5-fold (95% CI, 1.1- to 2.4-fold). Renal clearance of fexofenadine was significantly decreased during cimetidine treatment to 61% (95% CI, 50%-98%) and during probenecid treatment to 27% (95% CI, 20%–58%) but not during verapamil treatment. Conclusion: This study suggests that verapamil increases fexofenadine exposure probably because of an increase in bioavailability through P-glycoprotein inhibition and that probenecid slightly increases the area under the plasma concentration-time curve of fexofenadine as a result of a pronounced reduction in renal clearance. However, it may be difficult to explain these interactions by simple inhibitory mechanisms on target transporters. [ABSTRACT FROM AUTHOR]

Lansoprazole is a substrate of CYP2C19 and CYP3A4. The aim of this study was to compare the inhibitory effects of fluvoxamine, an inhibitor of CYP2C19, on the metabolism of lansoprazole between CYP2C19 genotypes. Eighteen volunteers—of whom 6 were homozygous extensive metabolizers (EMs), 6 were heterozygous EMs, and 6 were poor metabolizers (PMs) for CYP2C19—received three 6-day courses of either daily 50 mg fluvoxamine or placebo in a randomized fashion with a single oral 60-mg dose of lansoprazole on day 6 in all cases. Plasma concentrations of lansoprazole and its metabolites, 5-hydroxylansoprazole and lansoprazole sulfone, were monitored up to 24 hours after the dosing. During placebo administration, there was a significant difference in the area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) of lansoprazole between CYP2C19 genotypes. Fluvoxamine treatment increased AUC0-∞ of lansoprazole by 3.8-fold (P < .01) in homozygous EMs and by 2.5-fold (P < .05) in heterozygous EMs, whereas no difference in any pharmacokinetic parameters was found in PMs. There was a significant difference in the fluvoxamine-mediated percentage increase in the AUC0-∞ of lansoprazole between CYP2C19 genotypes. The present study indicates that there are significant drug interactions between lansoprazole and fluvoxamine in EMs. CYP2C19 is predominantly involved in lansoprazole metabolism in EMs. [ABSTRACT FROM PUBLISHER]

An in vitro study has recently suggested that a proton pump inhibitor, omeprazole, is a modest substrate of P-glycoprotein. Several studies have shown P-glycoprotein is involved in the absorption and excretion of fexofenadine. Therefore, we examined the effect of fexofenadine on the pharmacokinetics of omeprazole. Eight healthy volunteers participated in this study. They received a single oral dose of 40 mg omeprazole before and after 60 mg fexofenadine (10 doses over 6 days). Blood samplings were performed up to 8 hr after each dosing. Plasma concentrations of omeprazole and its two metabolites were quantified with high-performance liquid chromatography. In addition, the effect of fexofenadine on P-glycoprotein function was examined by flow cytometry using rhodamine 123 and CD56-positive lymphocytes. Comparison of the pharmacokinetic parameters of omeprazole before and after fexofenadine revealed that there were no differences in peak concentration, time to peak concentration, area under the time concentration curve up to 8 hr, and elimination half-life. There were also no differences in these pharmacokinetic parameters for the two metabolites of omeprazole. Flow cytometric analysis revealed that fexofenadine did not inhibit the efflux of rhodamine 123. This study indicated that there was probably no drug interaction between omeprazole and fexofenadine, which might be due to less contribution of P-glycoprotein to omeprazole absorption, insufficient inhibitory effect of fexofenadine on P-glycoprotein, or the involvement of other transporters such as organic anion transporting polypeptides. [ABSTRACT FROM AUTHOR]