Tsukasa Uno

Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics

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.

Limited frequency of the CYP2C19*17 allele and its minor role in a Japanese population

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT A novel CYP2C19 gene variant, CYP2C19*17, is associated with increased metabolic activity. Ethnic differences in the frequency of the variant allele have been reported. However, the frequency of the CYP2C19*17 allele has not been studied in the Japanese population. WHAT THIS STUDY ADDS In a population of 265 healthy Japanese subjects, a low frequency (1.3%) of the CYP2C19*17 allele was observed. The limited frequency of the *17 allele and the absence of a subject homozygous for *17 indicated that CYP2C19*17 would play a minor role in a Japanese population. AIMS We investigated the CYP2C19*17 allelic frequency in Japanese subjects, and evaluated whether CYP2C19*17 is an important determinant of interindividual variability of CYP2C19 activity. METHODS We enrolled 265 subjects to determine their CYP2C19 genotype and plasma metabolic ratio following a single dose of 40 mg omeprazole. RESULTS Seven subjects heterozygous for CYP2C19*17 and no *17/*17 subjects resulted in the CYP2C19*17 frequency being 1.3%. These heterozygotes had moderate metabolic activities when compared with the metabolic ratio of the other subjects. CONCLUSIONS The low frequency of CYP2C19*17 and the absence of *17/*17 indicates that CYP2C19*17 plays a minor role in the Japanese population.

Effects of Fluvoxamine on Lansoprazole Pharmacokinetics in Relation to CYP2C19 Genotypes

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.

The different effects of itraconazole on the pharmacokinetics of fexofenadine enantiomers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Recently, we have shown that the plasma concentration of R-fexofenadine is greater than that of the S-enantiomer. Although itraconazole co-administration is known to increase the bioavailability of a racemic mixture of fexofenadine, little is known about the stereoselective inhibition of P-gp activity by itraconazole. WHAT THIS STUDY ADDS This study indicates that the stereoselective pharmacokinetics of fexofenadine are due to P-gp-mediated transport and its stereoselectivity is altered by itraconazole, a an inhibitor of P-gp. AIMS The aim of this study was to determine the inhibitory effect of itraconazole, a P-glycoprotein (P-gp) inhibitor, on the stereoselective pharmacokinetics of fexofenadine. METHODS A two-way double-blind, placebo-controlled crossover study was performed with a 2-week washout period. Twelve healthy volunteers received either itraconazole 200 mg or matched placebo in a randomized fashion with a single oral dose of fexofenadine 60 mg simultaneously. The plasma concentrations and the amount of urinary excretion (Ae) of fexofenadine enantiomers were measured up to 24 h after dosing. RESULTS After placebo administration, mean AUC(0,24 h) of S- and R-fexofenadine was 474 ng ml(-1) h (95% CI 311, 638) and 798 ng ml(-1) h (95% CI 497, 1101), respectively. Itraconazole affected the pharmacokinetic parameters of S-fexofenadine more, and increased AUC(0,24 h) of S-fexofenadine and R-fexofenadine by 4.0-fold (95% CI of differences 2.8, 5.3; P < 0.001) and by 3.1-fold (95% CI of differences 2.2, 4.0; P = 0.014), respectively, and Ae(0,24 h) of S-fexofenadine and R-fexofenadine by 3.6-fold (95% CI of differences 2.6, 4.5; P < 0.001) and by 2.9-fold (95% CI of differences 2.1, 3.8; P < 0.001), respectively. Additionally, the R : S ratio for AUC(0,24 h) and Ae(0,24 h) were significantly reduced in the itraconazole phase, while t(max), t(1/2) and renal clearance were constant during the study. CONCLUSIONS This study indicates that the stereoselective pharmacokinetics of fexofenadine are due to P-gp-mediated transport and its stereoselectivity is altered by itraconazole, a P-gp inhibitor. However, further study will be needed because the different affinities of the two enantiomers for P-gp have not been supported by in vitro studies.

Influence of drug-transporter polymorphisms on the pharmacokinetics of fexofenadine enantiomers

This study investigated an association of SLCO (encoding organic anion-transporting polypeptides (OATP), 1B1, 1B3, and 2B1), ABCB1 (P-glycoprotein (P-gp)), ABCC2 multidrug resistance protein 2 (MRP2), and ABCG2 (breast cancer resistance protein (BCRP)) polymorphisms with fexofenadine enantiomer pharmacokinetics after an oral dose of fexofenadine (60 mg) in 24 healthy subjects. The area under the plasma concentration-time curve (AUC0–24) of S-fexofenadine, but not R-fexofenadine, was significantly lower in subjects with a SLCO2B1*1/*1 allele as compared to subjects with a *3 allele (p = 0.031). The AUC0–24 of S-fexofenadine was significantly lower in subjects with a wild-type combination of SLCO2B1*1/*1/ABCB1 1236CC, SLCO2B1*1/*1/ABCB1 3435CC, SLCO2B1*1/*1/ABCC2 -24CC, and ABCB1 1236CC/3435CC/ABCC2 -24CC compared to other polymorphic genotypes (p = 0.010, 0.033, 0.022, and 0.036, respectively), whereas there was no difference in the AUC0–24 between the SLCO1B1/1B3 plus ABCB1 and ABCC2 groups. The pharmacokinetic properties of S-fexofenadine are affected by a single polymorphism of SLCO2B1 in combination with several polymorphisms of ABCB1 C1236T, C3435T, and ABCC2 C-24T. However, the ABCG2 polymorphism was not associated with fexofenadine pharmacokinetics. These findings suggest that a combination of multiple transporters, including OATP, P-gp, and MRP2, reacts strongly to fexofenadine exposure in the small intestine and liver, resulting in different dispositions of both enantiomers.

Effect of Grapefruit Juice in Relation to Human Pharmacokinetic Study

Grapefruit juice (GFJ) interacts with a number of drugs, and can alter pharmacokinetics parameters of the drugs. As for these interactions, most reports have focused on the elevation of drug bioavailability by GFJ, but a few recent reports have indicated that GFJ reduced the absorption of drugs not metabolized by cytochrome P450 (CYP). The predominant mechanisms of GFJ-drug interaction are thought to be due primarily to the inhibition of intestinal CYP3A4 activity without an apparent inhibition of hepatic CYP3A4. GFJ is also an inhibitor of P-glycoprotein, an efflux pump in intestinal cell wall enterocytes, although clinical support for this mechanism remains unclear. In addition, GFJ has recently been shown to be a potent in vitro inhibitor of the organic anion-transporting polypeptides (OATP) 1A2, intestinal uptake transporters of structurally anionic drugs. It is therefore noteworthy that intestinal OATPs-mediated drug uptake are reduced by GFJ. The furanocoumarins, major active ingredients in relation to GFJ-drug interaction, were detected in fresh grapefruit, commercial GFJ and seville orange juice. However, the specific furanocoumarins responsible for the inhibition of CYP3A4 activity in in vitro study have yet to be fully determined and corresponded with GFJ effects in in vivo study. This article summarizes our data concerning GFJ-drug interaction and many GFJ-drug effects, and reviews the mechanism of this interaction, possible active ingredients and clinical implications.

Enantioselective disposition of fexofenadine with the P-glycoprotein inhibitor verapamil

AIMS 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. CONCLUSION 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.

The Role of Cytochrome P2C19 in R-warfarin Pharmacokinetics and its Interaction With Omeprazole

Previous studies reported omeprazole to be an inhibitor of cytochrome P450 (CYP) 2C19 and suggested the pharmacokinetic interaction of omeprazole with R-warfarin. The aim of this study was to compare possible effects of omeprazole on the stereoselective pharmacokinetics and pharmacodynamics of warfarin between CYP2C19 genotypes. Seventeen subjects, of whom 10 were homozygous extensive metabolizers (hmEMs) and seven were poor metabolizers (PMs) for CYP2C19, were enrolled in this randomized crossover study, and they ingested 20 mg omeprazole or placebo once daily for 11 days. On day 7, they administered a single dose of 10 mg racemic warfarin. The plasma concentrations of warfarin enantiomers and prothrombin time expressed as international normalized ratio were monitored up to 120 hours. During the placebo phase, area under the plasma concentration-time curve (AUC) and elimination half-life (t1/2) of R-warfarin in PMs was significantly greater than those in hmEMs (AUC[0-∞], 42,938/34,613 ng*h/mL [PM/hmEM], P = 0.004; t1/2, 48.8/40.8 hours [PM/hmEM], P = 0.013). Omeprazole treatment significantly increased the AUC(0-∞) (41,387 ng*h/mL, P = 0.004) and t1/2 (46.4 hours, P = 0.017) of R-warfarin in hmEMs to levels comparable to those in the PMs. There were no differences in S-warfarin pharmacokinetics between the CYP2C19 genotypes (AUC[0-∞], 15,851/16,968 ng*h/mL [PM/hmEM]; t1/2, 22.7/25.4 h [PM/hmEM]), or between the two treatment phases (AUC[0-∞], 14,756/18,166 ng*h/mL [PM/hmEM]; t1/2, 27.0/25.4 hours [PM/hmEM] in the omeprazole phase) as well as anticoagulant effects. These results indicate that CYP2C19 activity was one of determinants on the R-warfarin disposition because the pharmacokinetics of warfarin enantiomers were different between the CYP2C19 genotypes and the omeprazole affected the R-warfarin pharmacokinetics of CYP2C19 in only hmEMs. However, the phamacodynamic effect of the interaction of warfarin with omeprazole would be of minor clinical significance.

Effects of the CYP2D6*10 Allele on the Steady-State Plasma Concentrations of Aripiprazole and Its Active Metabolite, Dehydroaripiprazole, in Japanese Patients With Schizophrenia

The CYP2D6*10(*10) allele that causes decreased CYP2D6 activity is present in Asians with a high frequency of approximately 50%. We studied the effects of the *10 allele on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole. The subjects were 63 Japanese patients with schizophrenia who had only the wild-type or *10 alleles. Twenty-seven patients were homozygous for the wild-type allele, 31 were heterozygous, and five were homozygous for the *10 allele. All patients had been receiving the fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 40) and 12 mg (n = 23). No other drugs except biperiden and flunitrazepam were coadministered. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. The mean ± standard deviation values of concentration/dose ratios of aripiprazole in the patients with zero, one, and two *10 alleles were 9.0 ± 2.9, 12.7 ± 4.4, and 19.0 ± 6.8 ng/mL/mg, respectively, and those values for dehydroaripiprazole were 4.9 ± 1.6, 5.9 ± 1.7, and 5.9 ± 1.9 ng/mL/mg, respectively. The respective values for the sum of aripiprazole and dehydroaripiprazole were 13.9 ± 4.3, 18.6 ± 5.9, and 24.6 ± 8.5 ng/mL/mg. The mean concentration/dose ratios of aripiprazole were significantly (P < 0.01 or P < 0.001) different among the three genotype groups. The values for the sum of aripiprazole and dehydroaripiprazole were significantly higher in patients with one (P < 0.01) and two (P < 0.001) *10 alleles compared with those with zero *10 alleles. This study suggests that the *10 allele plays an important role in controlling the steady-state plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole in Asian subjects.

The effect of CYP2C19 genotypes on the pharmacokinetics of warfarin enantiomers

The aim of this study was to elucidate the pharmacokinetics and pharmacodynamics of warfarin enantiomers in relation to cytochrome P450 2C19 (CYP2C19) genotypes.Fourteen subjects, of whom seven were homozygous extensive metabolizers (hmEMs) and seven were poor metabolizers (PMs) for CYP2C19, were enrolled. After a single oral 10 mg dose of racemic warfarin, the plasma concentrations of the warfarin enantiomers and prothrombin time expressed as international normalized ratio (PT‐INR) were measured over the course of 120 h.The mean plasma concentrations and elimination half‐life of (R)‐warfarin of all the subjects were about 2‐fold greater than those of (S)‐warfarin. Additionally, the area under the plasma concentration–time curve from zero to infinity (AUC0–∞) and the elimination half‐life of (R)‐warfarin in PMs were significantly greater than those in hmEMs (P = 0·0005 and P = 0·0101 respectively). The S/R ratios of AUC of warfarin enantiomers were 0·51 in hmEMs and 0·37 in PMs (P = 0·0052). Whereas no difference was found in all pharmacokinetic parameters of (S)‐warfarin in hmEMs compared with PMs. No significant difference in PT‐INR, used as a measure of anticoagulant effect, was found between the hmEMs and PMs.These results show that CYP2C19 activity is important in the pharmacokinetics of (R)‐warfarin. However, when warfarin is administered as a racemate, this difference is not translated into any significant effect in the pharmacodynamics of warfarin.