Omeprazole hydroxylation is inhibited by a single dose of moclobemide in homozygotic EM genotype for CYP2C19

AIMS: The pharmacokinetics of omeprazole and its metabolites in healthy subjects were evaluated to determine if a single dose of moclobemide inhibited CYP2C19 activity. METHODS: Sixteen volunteers, of whom eight were extensive metabolizers (EM) and eight were poor metabolizers for CYP2C19, participated in two studies. Venous blood samples were collected for 24 h after oral ingestion of 40 mg omeprazole with or without 300 mg moclobemide coadministration. The pharmacokinetic change of omeprazole, omeprazole sulphone and 5-hydroxyomeprazole concentrations were assessed to test for an interaction between omeprazole and moclobemide. RESULTS: The coadministration of moclobemide in EMs approximately doubled the mean AUC (from 1834 to 3760 ng ml(-1) h) and C(max) (from 987 to 1649 ng ml(-1)) of omeprazole, and increased the AUC of omeprazole sulphone without changing AUC ratio of omeprazole to omeprazole sulphone. Moclobemide coadministration more than doubled the AUC ratio of omeprazole to 5-hydroxyomeprazole (from 2.5 to 5.3) in EMs, too. There was a significant decrease in Cmax and AUC of 5-hydroxyomeprazole in PMs but no significant changes were seen in the results for omeprazole and omeprazole sulphone AUCs. CONCLUSIONS: A single dose of moclobemide resulted in significant suppression of CYP2C19 activity in EMs. We conclude that physicians prescribing moclobemide should pay attention to its pharmacokinetic interactions even on the first day of coadministration with CYP2C19 substrates.     

Different effects of fluvoxamine on rabeprazole pharmacokinetics in relation to CYP2C19 genotype status

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,infinity) 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,infinity) 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,infinity) 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.     

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 (AUC(0-infinity)) of lansoprazole between CYP2C19 genotypes. Fluvoxamine treatment increased AUC(0-infinity) 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 AUC(0-infinity) 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.     

Effects of clarithromycin on lansoprazole pharmacokinetics between CYP2C19 genotypes

AIMS: 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 between CYP2C19 genotypes. METHODS: 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. RESULTS: During placebo administration, the mean AUC0, infinity 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 increased Cmax by 1.47-fold, 1.71-fold and 1.52-fold and AUC0, infinity 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 as Cmax, AUC0, infinity or elimination half-life did not differ between the three CYP2C19 genotypes. CONCLUSIONS: The present study indicates that there are significant drug interactions between lansoprazole and clarithromycin in all CYP2C19 genotype groups probably through CYP3A inhibition. The bioavailability of lansoprazole might, to some extent, be increased through inhibition of P-glycoprotein during clarithromycin treatment.     

Inhibitory effect of troleandomycin on the metabolism of omeprazole is CYP2C19 genotype-dependent

1. Eighteen healthy CYP2C19 genotyped male subjects were administered a 20-mg oral dose of omeprazole (OP) alone or received troleandomycin (TAO) 500 mg daily for 2 days before the dose of OP was administered. Blood samples were obtained and OP 5-hydroxyomeprazole (5-OH-OP) and OP sulfone in plasma were determined by reversed-phase HPLC. 2. The mean C(max), AUC and CL for OP in poor metabolizers (PMs) were greater with TAO than without TAO. The C(max) and AUC of 5-OH-OP in PMs were significantly (p < 0.05) less with TAO than without TAO. The differences in 5-OH-OP between heterozygous extensive metabolizers (EMs) with TAO versus without TAO were similar to those observed in PMs, except for the AUC. However, in homozygous EMs, there were no statistical differences for the effect of TAO. 3. The effect of TAO on the metabolism of OP and its two principal metabolites differs in different genotype groups of CYP2C19. CYP3A4 not only plays a dominant role in the formation of OP sulfone, but also it contributes to the 5-hydroxylation of OP. Both CYP2C19 and CYP3A contribute to the further elimination of 5-OH-OP and OP sulfone.     

Inhibitory effect of troleandomycin on the metabolism of omeprazole is CYP2C19 genotype-dependent

1. Eighteen healthy CYP2C19 genotyped male subjects were administered a 20-mg oral dose of omeprazole (OP) alone or received troleandomycin (TAO) 500 mg daily for 2 days before the dose of OP was administered. Blood samples were obtained and OP 5-hydroxyomeprazole (5-OH-OP) and OP sulfone in plasma were determined by reversed-phase HPLC. 2. The mean C max, AUC and CL for OP in poor metabolizers (PMs) were greater with TAO than without TAO. The C max and AUC of 5-OH-OP in PMs were significantly (p < 0.05) less with TAO than without TAO. The differences in 5-OH-OP between heterozygous extensive metabolizers (EMs) with TAO versus without TAO were similar to those observed in PMs, except for the AUC. However, in homozygous EMs, there were no statistical differences for the effect of TAO. 3. The effect of TAO on the metabolism of OP and its two principal metabolites differs in different genotype groups of CYP2C19. CYP3A4 not only plays a dominant role in the formation of OP sulfone, but also it contributes to the 5-hydroxylation of OP. Both CYP2C19 and CYP3A contribute to the further elimination of 5-OH-OP and OP sulfone.     

An optimized methodology for combined phenotyping and genotyping on CYP2D6 and CYP2C19

A method for simultaneous phenotyping and genotyping for CYP2D6 and CYP2C19 was tested. Six healthy volunteers were selected (three extensive and three poor metabolisers for CYP2D6). CYP2D6 was probed with dextromethorphan and metoprolol and CYP2C19 was probed with omeprazole. Blood samples were collected and analysed for dextromethorphan, dextrorphan, metoprolol, alpha-hydroxymetoprol, omeprazole and 5-hydroxyomeprazole by HPLC. Genotyping was performed for both CYP2D6 and CYP2C19. Generally, plasma levels could be measured up to 8 h post-dose except for alpha-hydroxymetoprolol in poor metabolizers (PMs) and dextromethorphan in extensive metabolizers (EMs) (35% below quantification limit). The correlation between the metabolic ratio based on timed individual measurements and the metabolic ratio based on the AUC0-12 values was significant at 3 h post-dose for all probes. In conclusion, the following procedure is suggested: administer metoprolol (100 mg) and omeprazole (40 mg); after 3 h, take a blood sample to assess the genotype and the metabolic ratio for CYP2D6 (metoprolol over alpha-hydroxymetoprolol) and CYP2C19 (omeprazole over 5-hydroxyomeprazole) in plasma. With this procedure, all necessary information on the individual CYP2D6 and CYP2C19 metabolising capacity can be obtained in a practical, single-sample approach.     

The role of CYP2C19 in amitriptyline N-demethylation in Chinese subjects

OBJECTIVE: To determine the role of cytochrome P(450) (CYP)2C19 in N-demethylation of amitriptyline (AT) in healthy Chinese subjects.METHODS: One hundred and one subjects were genotyped for CYP2C19 using polymerase chain reaction-restriction fragment length polymorphism analysis. Twelve unrelated adult men (19.7+/-0.6 years, 61.8+/-3.8 kg) were chosen and orally given a single dose of 50 mg AT, and the blood samples were drawn from a forearm vein at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 h after AT administration. Plasma concentrations of AT and nortriptyline (NT) were determined using high-performance liquid chromatography with an ultraviolet detector.RESULTS: The mean area under the plasma concentration-time curve (AUC(AT)) of CYP2C19 poor metabolizers (PMs, n=6) was significantly higher than that of CYP2C19 extensive metabolizers (EMs, n=6) (2207+/-501 ng/ml x h(-1) vs 1596+/-406 ng/ml x h(-1), P<0.05). In contrast, the mean AUC(NT(0-)(infinity)()) of PMs was significantly lower than that of EMs (294+/-70 ng/ml x h(-1) vs 684+/-130 ng/ml x h(-1), P<0.0001). Other pharmacokinetic parameters such as clearance, half-life, maximum plasma concentration, and time to peak plasma concentration showed no significant difference between PMs and EMs (0.41+/-0.12 l /h x kg(-1) vs 0.50+/-0.15 l /h x kg(-1), 25.0+/-6.2 h vs 24.1+/-4.4 h, 96+/-25 ng/ml vs 75+/-27 ng/ml, 4.0+/-1.4 h vs 3.7+/-1.5 h, respectively).CONCLUSION: The genetic defects of CYP2C19 have a significant effect on AT pharmacokinetics, and CYP2C19 plays an important role in N-demethylation of AT in vivo at a clinically therapeutic dose.     

Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole

Aims To study the pharmacokinetics of three proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole, as well as any potential influence on CYP1A2 activity (measured by means of rate of caffeine metabolism) of these compounds at single dose and repeated dose administration.
Methods Fourteen healthy males, classified as 12 extensive metabolizers (EMs) and two poor metabolizers (PMs) according to the urinary S/R mephenytoin ratio, completed this open, randomized, three-way cross-over study. In each of the three 7-day treatment periods either omeprazole (20  mg), lansoprazole (30  mg) or pantoprazole (40  mg) in therapeutically recommended doses was administered once daily, and the pharmacokinetics of the proton pump inhibitors as well as the rate of caffeine metabolism was measured on days 1 and 7.
Results In the EMs there was an increase in AUC from day 1 to day 7 for omeprazole. In the PMs the AUC of both omeprazole and lansoprazole was unchanged during repeated dosing, while for pantoprazole there was a tendency to a slight decrease. The AUC at steady state was for all three proton pump inhibitors 5 fold higher in PMs compared with EMs, indicating that the same proportion of the dose, irrespective of compound, is metabolized by CYP2C19. No induction of CYP1A2 was evident for any of the compounds in either EMs or PMs.
Conclusions The ∼5 fold difference in AUC between EMs and PMs indicates that approximately 80% of the dose for all three proton pump inhibitors is metabolized by the polymorphically expressed CYP2C19. None of the three proton pump inhibitors, administered in therapeutically recommended doses, is an inducer of CYP1A2—neither in PMs nor in EMs.     

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-infinity], 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-infinity) (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-infinity], 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-infinity], 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.     

The (R)-omeprazole hydroxylation index reflects CYP2C19 activity in healthy Japanese volunteers

Purpose

Omeprazole has (R)- and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose (R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three CYP2C19 genotype groups in Japanese individuals.

Methods

Ninety healthy Japanese individuals were enrolled and classified into the three different CYP2C19 genotype groups: homozygous extensive metabolizers (hmEMs; n?=?34), heterozygous EMs (htEMs; n?=?44), and poor metabolizers (PMs; n?=?12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column.

Results

Mean plasma concentrations of (R)- and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of (R)-5-hydroxyomeprazole among CYP2C19 genotype groups, whereas no significant differences were observed in that of (S)-5-hydroxyomeprazole. Similarly, (R)-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI.

Conclusion

Our findings demonstrate that (R)-omeprazole HI correlated better with CYP2C19 genotype groups than racemic-omeprazole HI, and these results may be useful for classification among patients in CYP2C19 genotype groups prior to omeprazole treatment.     

The effect of aging on the relationship between the cytochrome P450 2C19 genotype and omeprazole pharmacokinetics

BACKGROUND AND OBJECTIVE: The metabolic activity of cytochrome P450 (CYP) 2C19 is genetically determined, and the pharmacokinetics of omeprazole, a substrate for CYP2C19, are dependent on the CYP2C19 genotype. However, a discrepancy between the CYP2C19 genotype and omeprazole pharmacokinetics was reported in patients with liver disease or advanced cancer. The objective of the present study was to evaluate the effect of aging on the relationship between the CYP2C19 genotype and its phenotype. METHODS: Twenty-eight elderly and 23 young Japanese volunteers were enrolled after being genotyped. Each subject received a single intravenous dose of omeprazole (10 mg and 20 mg for the elderly and the young groups, respectively) and blood samples were obtained up to 6 hours after dose administration to determine the plasma concentrations of omeprazole and its metabolites, 5-hydroxyomeprazole and omeprazole sulfone. Pharmacokinetic parameters were obtained by noncompartmental analysis. Linear regression models were used to examine the joint effects of covariates such as genotype, age, etc., on the pharmacokinetic parameters, and the pharmacokinetic parameters showing statistical significance were compared by ANOVA. RESULTS: There were significant differences between genotypes in the area under the plasma concentration-time curve of the young group and the elderly group. The number of mutation alleles and age were significant covariates for systemic clearance (CL), but age was the only significant covariate for volume of distribution at steady state (Vss). There were significant age- and genotype-related differences and a significant age x genotype interaction in CL (20.6+/-11.0/12.7+/-4.0/3.2+/-1.0 and 5.4+/-4.0/3.7+/-1.4/2.1+/-0.7 L/h for homozygous extensive metabolisers [EMs]/heterozygous EMs/poor metabolisers [PMs] of the young and the elderly groups, respectively). In Vss, a significant difference was found between the young and the elderly groups (219+/-115 and 107+/-44.5 mL/kg, respectively), but not between three genotypes (178+/-142, 173+/-79 and 110+/-51 mL/kg for homozygous EMs, heterozygous EMs and PMs, respectively). CONCLUSION: The elderly EMs showed wide variance in the in vivo CYP2C19 activity and were phenotypically closer to the elderly PMs than the young EMs were to the young PMs. Some of the elderly homozygous EMs, as well as heterozygous EMs, have a metabolic activity similar to PMs, and the CYP2C19 genotype may therefore not be as useful as phenotyping in the elderly.     

Effects of clarithromycin and verapamil on rabeprazole pharmacokinetics between CYP2C19 genotypes

Objective Rabeprazole as a proton pump inhibitor (PPI) is mainly reduced to rabeprazole thioether via a nonenzymatic pathway, with minor CYP2C19 and CYP3A4 involvement. The aim of this study was to compare possible effects of clarithromycin and verapamil as inhibitors of CYP3A4 on the pharmacokinetics of rabeprazole among CYP2C19 genotypes.Methods A three-way randomized, double-blind, placebo-controlled crossover study was performed. Nineteen volunteers, of whom six were homozygous extensive metabolizers (EMs), eight were heterozygous EMs, and five were poor metabolizers (PMs) for CYP2C19, received three 6-day courses of either daily 800 mg clarithromycin, 240 mg verapamil, or placebo in a randomized fashion, with a single oral dose of 20 mg rabeprazole on day 6 in all cases. Plasma concentrations of rabeprazole and rabeprazole thioether were monitored up to 24 h after the dosing.Results In the control phase, the AUC_0−∞ values for rabeprazole and rabeprazole thioether were 1,005±366 and 412±149 ng.h/ml in homozygous EMs, 1,108±340 and 491±245 ng.h/ml in heterozygous EMs, and 2,697±364 and 2,116±373 ng.h/ml in PMs, respectively. There were significant differences (p<0.001) in the AUC_0−∞ of rabeprazole and rabeprazole thioether among three different CYP2C19 genotypes. In the clarithromycin and verapamil phases, no significant differences were found in the pharmacokinetic parameters of rabeprazole compared with those in the control phase irrespective of CYP2C19 genotypes, whereas the AUC_0−∞ of rabeprazole thioether was significantly increased 2.8-fold and 2.3-fold in homozygous EMs (p<0.01), 2.0-fold and 2.0-fold in heterozygous EMs (p<0.05), and 1.6-fold and 1.9-fold in PMs (p<0.05), respectively. In each genotype group for CYP2C19, there were no statistical differences in the percent increase in those pharmacokinetic parameters between the clarithromycin and verapamil pretreatment phases.Conclusion The pharmacokinetic parameters of rabeprazole were not altered by clarithromycin or verapamil irrespective of the CYP2C19 genotypes. However, this result shows that both clarithromycin and verapamil significantly influence the disposition of rabeprazole by inhibiting the oxidation of the thioether, since the AUC_0−∞ of rabeprazole thioether that has no effect on acid secretion increased. Therefore, the pharmacokinetic interactions between rabeprazole and CYP3A4 or P-glycoprotein inhibitors have limited clinical significance.     

Finasteride 1 mg has no inhibitory effect on omeprazole metabolism in extensive and poor metabolizers for CYP2C19 in Japanese

Objective To examine the inhibitory effect of finasteride 1 mg on the metabolism of omeprazole in genetically determined extensive (EMs) and poor metabolizers (PMs) for CYP2C19 in young healthy Japanese male subjects.Methods Twenty-four volunteers participated in this study, among whom 12 were homozygous EMs and 12 were PMs for CYP2C19. A single center, controlled, randomized, open, crossover study with a 5 day washout between the two study periods was performed. Each of the six EMs and PMs received a single oral 20 mg dose of omeprazole on day 1 (treatment I). After a 5 day washout period, these subjects received 1 mg of finasteride once a day for three consecutive days, and a single oral 20 mg dose of omeprazole was co-administered on day 3 (treatment II). The 12 other EMs and PMs received treatments I and II in reverse. Plasma samples were collected for up to a 12 hours postdose of omeprazole, and the pharmacokinetic parameters of omeprazole were determined.Results The geometric mean ratio (GMR) for the AUC_{(0–12 hr)} of omeprazole when co-administered with finasteride/omeprazole alone is 1.13 (90%CI, 1.03, 1.25) and 0.96 (0.88, 1.05) in EMs and PMs, respectively. Finasteride did not significantly alter C_max, T_max and t_1/2 in both genotypes.Conclusion Finasteride 1 mg, widely used for the treatment of androgenetic alopecia in men, did not meaningfully increase omeprazole exposure (20 mg) in both EMs and PMs for CYP2C19. These results indicate that finasteride does not meaningfully inhibit CYP2C19 activity in vivo at the dose of 1 mg.     

Effect of the CYP2C19 oxidation polymorphism on fluoxetine metabolism in Chinese healthy subjects

AIMS: The study was designed to investigate whether genetically determined CYP2C19 activity affects the metabolism of fluoxetine in healthy subjects. METHODS: A single oral dose of fluoxetine (40 mg) was administrated successively to 14 healthy young men with high (extensive metabolizers, n=8) and low (poor metabolizers, n = 6) CYP2C19 activity. Blood samples were collected for 5-7 half-lives and fluoxetine, and norfluoxetine were determined by reversed-phase high performance liquid chromatography. RESULTS: Poor metabolizers (PMs) showed a mean 46% increase in fluoxetine peak plasma concentrations (Cmax, P < 0.001), 128% increase in area under the concentration vs time curve (AUC(0, infinity), P < 0.001), 113% increase in terminal elimination half-life (t(1/2)) (P < 0.001), and 55% decrease in CLo (P < 0.001) compared with extensive metabolizers (EMs). Mean +/- (s.d) norfluoxetine AUC(0, 192 h) was significantly lower in PMs than that in EMs (1343 +/- 277 vs 2935 +/- 311, P < 0.001). Mean fluoxetine Cmax and AUC(0, infinity) in wild-type homozygotes (CYP2C19*1/CYP2C19*1) were significantly lower than that in PMs (22.4 +/- 3.9 vs 36.7 +/- 8.9, P < 0.001; 732 +/- 42 vs 2152 +/- 492, P < 0.001, respectively). Mean oral clearance in individuals with the wild type homozygous genotype was significantly higher than that in heterozygotes and that in PMs (54.7 +/- 3.4 vs 36.0 +/- 8.7, P < 0.01; 54.7 +/- 3.4 vs 20.6 +/- 6.2, P < 0.001, respectively). Mean norfluoxetine AUC(0, 192 h) in PMs was significantly lower than that in wild type homozygotes (1343 +/- 277 vs 3163 +/- 121, P < 0.05) and that in heterozygotes (1343 +/- 277 vs 2706 +/- 273, P < 0.001), respectively. CONCLUSIONS: The results indicated that CYP2C19 appears to play a major role in the metabolism of fluoxetine, and in particular its N-demethylation among Chinese healthy subjects.     

Formation of omeprazole sulphone but not 5-hydroxyomeprazole is inhibited by grapefruit juice

AIMS: To determine the effect of grapefruit juice on omeprazole metabolism in vivo. METHODS: This was a randomized crossover study with a 2 week washout period. Omeprazole (20 mg) was taken orally by 13 healthy volunteers after an overnight fast with either grapefruit juice or water. Serial blood samples were obtained over 12 h and standardized meals were served 3 and 10 h after the administration of omeprazole. Plasma concentrations of omeprazole and its major metabolites, 5-hydroxyomeprazole and omeprazole sulphone, were determined by high performance liquid chromatography (h.p.l.c.). RESULTS: Mean area under the plasma concentration vs time curve (AUC) between 0 and 12 h for omeprazole sulphone was approximately 20% lower (P<0.01) in the group receiving grapefruit juice. There was no significant difference in the mean AUC of 5-hydroxyomeprazole or omeprazole. The AUC ratio of omeprazole sulphone to omeprazole, an index of CYP3A4 activity, was decreased by 33% (P<0.001) after administration of grapefruit juice whereas the AUC ratio of 5-hydroxyomeprazole to omeprazole, an index of CYP2C19 activity, did not differ between the two phases of the study. Although the time to peak concentration (tmax ) and terminal half-life (t1/2,z) of omeprazole and its two main metabolites were not altered, the peak concentration (Cmax ) of omeprazole sulphone was significantly reduced after administration of grapefruit juice. CONCLUSION: Administration of grapefruit juice decreased the formation of omeprazole sulphone but not 5-hydroxyomeprazole. These results indicate that activities of CYP3A4, but not of CYP2C19, are inhibited by the simultaneous administration of grapefruit juice.     

Absolute bioavailability and metabolism of omeprazole in relation to CYP2C19 genotypes following single intravenous and oral administrations

Objective The aim of this study was to evaluate the absolute bioavailability and the metabolism of omeprazole following single intravenous and oral administrations to healthy subjects in relation to CYP2C19 genotypes. Methods Twenty subjects, of whom 6 were homozygous extensive metabolizers (hmEMs), 8 were heterozygous EMs (htEMs) and 6 were poor metabolizers (PMs) for CYP2C19, were enrolled in this study. Each subject received either a single omeprazole 20 mg intravenous dose (IV) or 40 mg oral dose (PO) in a randomized fashion during 2 different phases. Results Mean omeprazole AUC (0,∞) was 1164, 3093 and 10511 ng h/mL after PO, and 1435, 2495 and 6222 ng h/mL after IV in hmEMs, htEMs and PMs, respectively. Therefore, the absolute bioavailability of omeprazole in PMs was significantly higher than that in hmEMs (p < 0.001) and htEMs (p < 0.001). Hydroxylation metabolic indexes after IV and PO were significantly lower in PMs than in hmEMs (p < 0.001) and htEMs (p < 0.001), and was correlated with the absolute bioavailability (p < 0.0001 for both IV and PO). Sulfoxidation metabolic index after IV was significantly different between the CYP2C19 genotypes, whereas no difference was found after a single oral dose. Conclusion This study indicates that the absolute bioavailability of omeprazole differs among the three different CYP2C19 genotypes after a single dose of omeprazole orally or intravenously. Hydroxylation metabolic index of omeprazole may be mainly attributable to the genotype of CYP2C19. As for the sulfoxidation metabolic index after a single oral dose, intestinal CYP3A may be contributed to omeprazole metabolism.     

Tolterodine does not affect the human in vivo metabolism of the probe drugs caffeine, debrisoquine and omeprazole

AIM: To investigate the in vivo effect of treatment with tolterodine on debrisoquine 4-hydroxylation (an index of CYP2D6 activity), omeprazole 5-hydroxylation (CYP2C19), omeprazole sulphoxidation (CYP3A4) and caffeine N3-demethylation (CYP1A2). METHODS: Twelve healthy male volunteers (eight extensive metabolisers [EMs] and four poor metabolisers [PMs] with respect to CYP2D6) received 4 mg tolterodine L-tartrate orally twice daily for 6 days. All subjects were EMs with respect to CYP2C19. The subjects received single oral doses of debrisoquine (10 mg), omeprazole (20 mg) and caffeine (100 mg) for determination of the appropriate metabolic ratios (MR). The drugs were given on separate consecutive days, before, during and after the co-administration of tolterodine. RESULTS: Mean serum tolterodine concentrations were 5-10 times higher in PMs than in EMs. Serum concentrations of the active 5-hydroxymethyl metabolite of tolterodine, 5-HM, were not quantifiable in PMs. The mean MR of debrisoquine (95% confidence interval) during tolterodine treatment was 0.50 (0.25-0.99) and did not differ statistically from the values before [0.49 (0.20-1.2)] and after tolterodine administration [0.46 (0.14-1.6)] in EMs. The mean MR of omeprazole hydroxylation and sulphoxidation or caffeine metabolism were not changed in the presence of tolterodine in either EMs or PMs. Debrisoquine and caffeine had no significant effect on the AUC(1,3 h) of either tolterodine or 5-HM, but during omeprazole administration small decreases (13-19%) in these parameters were seen. CONCLUSIONS: Tolterodine, administered at twice the expected therapeutic dosage, did not change the disposition of the probe drugs debrisoquine, omeprazole and caffeine and thus had no detectable effect on the activities of CYPs 2D6, 2C19, 3A4 and 1A2. Alteration of the metabolism of substrates of these enzymes by tolterodine is unlikely to occur.     

Influence of CYP2C19 on the relationship between pharmacokinetics and intragastric pH of omeprazole administered by successive intravenous infusions in Chinese healthy volunteers

Objectives

To explore the effect of cytochrome P450 2C19 (CYP2C19) polymorphisms on the relationship between the pharmacokinetics and pharmacodynamics of omeprazole administered by intravenous successive infusions in Chinese healthy volunteers.

Methods

A total of 21 subjects [7 homozygous extensive metabolizers (homEMs), 9 heterozygous extensive metabolizers (hetEMs), 5 poor metabolizers (PMs)] received a 5-day course of omeprazole (40 mg) administered as a single dose daily during a 30-min period. Plasma concentrations were monitored by sampling at very short intervals for the first 8.5 h post-omeprazole administration and at 24 h post-administration, and intragastric pH was recorded on days 1 and 5.

Results

After a single dose, both the area under the plasma concentration–time curve (AUC) and peak concentration (C_max) were higher in PMs than in EMs. Both the mean half-life (t_½) and total clearance in PMs were significantly higher and lower than those in homEMs and EMs, respectively. Mean AUC and C_max ratios in homEMs, hetEMs, and PMs were 1.0:1.1:1.4 and 1.0:1.0:1.1, respectively. Relative to the values determined after a single dose in EMs, after repeated doses, the intragastric pH, AUC, C_max, and t_½ had increased significantly, while the total clearance had decreased significantly. Mean AUC and C_max ratios in homEMs, hetEMs, and PMs were 1.4:1.4:1.5 and 1.2:1.2:1.3, respectively, compared to those of a single dose. The mean intragastric pH was significantly higher in PMs than in EMs after the fifth dose.

Conclusions

There is a relationship between the pharmacokinetics and pharmacodynamics of omeprazole, with the latter depending in part on the duration of administration as evidenced by a higher AUC or C_max and intragastric pH resulting from repeated dosing.     

Pharmacogenetic roles of CYP2C19 and CYP2B6 in the metabolism of R- and S-mephobarbital in humans

OBJECTIVES AND METHODS: We assessed the relationship between the metabolism of R- and S-mephobarbital (MPB) and genetic polymorphisms of cytochrome P450 (CYP) 2C19 and CYP2B6. Nine homozygous extensive metabolizers (homo-EMs, 2C19*1/2C19*1) of CYP2C19, ten heterozygous EMs (hetero-EMs, 2C19*1/2C19*2, 2C19*1/2C19*3) and eleven poor metabolizers (PMs, 2C19*2/2C19*2, 2C19*3/2C19*3, 2C19*2/2C19*3) recruited from a Japanese population, received an oral 200 mg-dose of racemic MPB. Blood and urine samples were collected, and R-MPB, S-MPB and the metabolites, phenobarbital (PB) and 4'-hydroxy-MPB, were measured. Each subject was also genotyped for CYP2B6 gene. RESULTS: The mean area under the plasma concentration-time curve (AUC) of R-MPB was 92-fold greater in PMs than in homo-EMs. R/S ratios for AUC of MPB were much higher in PMs than in EMs (homo- and hetero-). The cumulative urinary excretion of 4'-hydroxy-MPB up to 24 h postdose was 21-fold less in PMs than in homo-EMs. The metabolic ratio of AUCPB/(AUCS-MPB + AUCR-MPB) was higher in PMs than in EMs (homo- and hetero-). In addition, this metabolic ratio was lower in the carriers of CYP2B6*6 compared with that in its non-carriers. CONCLUSIONS: Our results indicate that the 4'-hydroxylation of R-MPB is mediated via CYP2C19 and that the rapid 4'-hydroxylation of R-MPB results in a marked difference in the pharmacokinetic profiles between R-MPB and S-MPB in the different CYP2C19 genotypic individuals. In addition, a minor fraction of the interindividual variability in PB formation from MPB may be explainable by the CYP2B6*6 allele.