CYP2C8 but not CYP3A4 is important in the pharmacokinetics of montelukast

AIM

According to product information, montelukast is extensively metabolized by CYP3A4 and CYP2C9. However, CYP2C8 was also recently found to be involved. Our aim was to study the effects of selective CYP2C8 and CYP3A4 inhibitors on the pharmacokinetics of montelukast.

METHODS

In a randomized crossover study, 11 healthy subjects ingested gemfibrozil 600 mg, itraconazole 100 mg (first dose 200 mg) or both, or placebo twice daily for 5 days, and on day 3, 10 mg montelukast. Plasma concentrations of montelukast, gemfibrozil, itraconazole and their metabolites were measured up to 72 h.

RESULTS

The CYP2C8 inhibitor gemfibrozil increased the AUC(0,∞) of montelukast 4.3-fold and its t_1/2 2.1-fold (P < 0.001). Gemfibrozil impaired the formation of the montelukast primary metabolite M6, reduced the AUC and C_max of the secondary (major) metabolite M4 by more than 90% (P < 0.05) and increased those of M5a and M5b (P < 0.05). The CYP3A4 inhibitor itraconazole had no significant effect on the pharmacokinetic variables of montelukast or its M6 and M4 metabolites, but markedly reduced the AUC and C_max of M5a and M5b (P < 0.05). The effects of the gemfibrozil-itraconazole combination on the pharmacokinetics of montelukast did not differ from those of gemfibrozil alone.

CONCLUSIONS

CYP2C8 is the dominant enzyme in the biotransformation of montelukast in humans, accounting for about 80% of its metabolism. CYP3A4 only mediates the formation of the minor metabolite M5a/b, and is not important in the elimination of montelukast. Montelukast may serve as a safe and useful CYP2C8 probe drug.     

The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects

AIMS: Rosiglitazone, a thiazolidinedione antidiabetic medication used in the treatment of Type 2 diabetes mellitus, is predominantly metabolized by the cytochrome P450 (CYP) enzyme CYP2C8. The anti-infective drug trimethoprim has been shown in vitro to be a selective inhibitor of CYP2C8. The purpose of this study was to evaluate the effect of trimethoprim on the CYP2C8 mediated metabolism of rosiglitazone in vivo and in vitro. METHODS: The effect of trimethoprim on the metabolism of rosiglitazone in vitro was assessed in pooled human liver microsomes. The effect in vivo was determined by evaluating rosiglitazone pharmacokinetics in the presence and absence of trimethoprim. Eight healthy subjects (four men and four women) completed a randomized, cross-over study. Subjects received single dose rosiglitazone (8 mg) in the presence and absence of trimethoprim 200 mg given twice daily for 5 days. RESULTS: Trimethoprim inhibited rosiglitazone metabolism both in vitro and in vivo. Inhibition of rosiglitazone para-hydroxylation by trimethoprim in vitro was found to be competitive with apparent K(i) and IC(50) values of 29 microm and 54.5 microm, respectively. In the presence of trimethoprim, rosiglitazone plasma AUC was increased by 31% (P = 0.01) from 2774 +/- 645 microg l(-1) h to 3643 +/- 1051 microg l(-1) h (95% confidence interval (CI) for difference 189, 1549), and half-life was increased by 27% (P = 0.006) from 3.3 +/- 0.5 to 4.2 +/- 0.8 h (95% CI for difference 0.36, 1.5). Trimethoprim reduced the para-O-sulphate rosiglitazone/rosiglitazone and the N-desmethylrosiglitazone/rosiglitazone AUC(0-24) ratios by 22% and 38%, respectively. CONCLUSIONS: These results indicate that trimethoprim is a competitive inhibitor of CYP2C8-mediated rosiglitazone metabolism in vitro and that trimethoprim administration increases plasma rosiglitazone concentrations in healthy subjects.     

Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects

AIMS: Fungal infection is a significant comorbidity in patients with diabetes mellitus, and ketoconazole, an antifungal agent, causes a number of drug interactions with coadministered drugs. Rosiglitazone is a novel thiazolidinedione antidiabetic drug, mainly metabolized by CYP2C8 and to a lesser extent CYP2C9. We investigated the possible effect of ketoconazole on the pharmacokinetics of rosiglitazone in humans. METHODS: Ten healthy Korean male volunteers were treated twice daily for 5 days with 200 mg ketoconazole or with placebo, using a randomized, open-label, two-way crossover study. On day 5, a single dose of 8 mg rosiglitazone was administered orally, and plasma rosiglitazone concentrations were measured. RESULTS: Ketoconazole increased the mean area under the plasma concentration-time curve for rosiglitazone by 47%[P = 0.0003; 95% confidence interval (CI) 23, 70] and the mean elimination half-life from 3.55 to 5.50 h (P = 0.0003; 95% CI in difference 1.1, 2.4). The peak plasma concentration of rosiglitazone was increased by ketoconazole treatment by 17% (P = 0.03; 95% CI 5, 29). The apparent oral clearance of rosiglitazone decreased by 28% after ketoconazole treatment (P = 0.0005; 95% CI 18, 38). CONCLUSIONS: This study revealed that ketoconazole affected the disposition of rosiglitazone in humans, probably by the inhibition of CYP2C8 and CYP2C9, leading to increasing rosiglitazone concentrations that could increase the efficacy of rosiglitazone or its adverse events.     

Montelukast and zafirlukast do not affect the pharmacokinetics of the CYP2C8 substrate pioglitazone

Objective Pioglitazone, a thiazolidinedione antidiabetic drug, is metabolised mainly by the cytochrome P450 (CYP) 2C8 enzyme. The leukotriene receptor antagonists montelukast and zafirlukast have potently inhibited CYP2C8 activity and the metabolism of pioglitazone in vitro. Our objective was to determine whether montelukast and zafirlukast increase the plasma concentrations of pioglitazone in humans.Methods In a randomised, double-blind crossover study with three phases and a washout period of 3 weeks, 12 healthy volunteers took either 10 mg montelukast once daily and placebo once daily, or 20 mg zafirlukast twice daily, or placebo twice daily, for 6 days. On day 3, they received a single oral dose of 15 mg pioglitazone. The plasma concentrations of pioglitazone and its metabolites M-IV, M-III, M-V and M-XI were measured for 96 h.Results The total area under the plasma concentration-time curve of pioglitazone during the montelukast and zafirlukast phases was 101% (range 71–143%) and 103% (range 78–146%), respectively, of that during the placebo phase. Also, the peak plasma concentration and elimination half-life of pioglitazone remained unaffected by montelukast and zafirlukast. There were no statistically significant differences in the pharmacokinetics of any of the metabolites of pioglitazone between the phases.Conclusions Montelukast and zafirlukast do not increase the plasma concentrations of pioglitazone, indicating that their inhibitory effect on CYP2C8 is negligible in vivo, despite their strong inhibitory effect on CYP2C8 in vitro. The results highlight the importance of in vivo interaction studies and of the incorporation of relevant pharmacokinetic properties of drugs, including plasma protein binding data, to in vitro-in vivo interaction predictions.Supported by grants from the National Technology Agency (Tekes), the Helsinki University Central Hospital Research Fund and the Sigrid Jusélius Foundation, Finland.     

Pioglitazone, an in vitro inhibitor of CYP2C8 and CYP3A4, does not increase the plasma concentrations of the CYP2C8 and CYP3A4 substrate repaglinide

Objective Pioglitazone, a thiazolidinedione antidiabetic, inhibits cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes in vitro. Repaglinide, a meglitinide analogue antidiabetic, is metabolised by CYP2C8 and CYP3A4. In patients with type 2 diabetes, the pioglitazone-repaglinide combination has acted synergistically on glycaemic parameters. Our aim was to determine whether pioglitazone increases the plasma concentrations of repaglinide. Methods In a randomized, 2-phase cross-over study, 12 healthy volunteers received 30 mg pioglitazone or placebo once daily for 5 days. On day 5, they ingested a single 0.25 mg dose of repaglinide 1 h after the last pretreatment dose. Plasma repaglinide and pioglitazone, and blood glucose concentrations were measured for 12 h. Results During the pioglitazone phase, the mean peak plasma repaglinide concentration (C_max) and the total area under the concentration-time curve [AUC(0-∞)] of repaglinide were 100% (range 53–157%, P=0.99) and 90% (range 63–120%, P=0.22), respectively, of those during the placebo phase. Also the half-life of repaglinide was unaffected, but the median peak time of repaglinide was shortened from 40 min to 20 min by pioglitazone (P=0.014). The short-term pioglitazone administration did not modify the blood glucose-lowering effect of a single dose of repaglinide. Conclusions Pioglitazone does not increase the plasma concentrations of repaglinide, indicating that the inhibitory effect of pioglitazone on CYP2C8 and CYP3A4 is very weak in vivo, probably due to its extensive plasma protein binding. The synergistic effect of repaglinide and pioglitazone on the glycaemic parameters, seen in patients with type 2 diabetes during their long-term use, is unlikely to be caused by inhibition of repaglinide metabolism by pioglitazone.     

Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population

Objective The purpose of the study was to study the distribution of poor and extensive metabolizers of CYP2C19 and CYP2D6 and to genotype for CYP2C8 and CYP2C9 among 312 randomly selected Faroese.Methods and results The participants were phenotyped for CYP2D6 with the use of sparteine. The distribution of the sparteine metabolic ratio (sparteine/didehydrosparteines) was bimodal, and 14.5% (n=44; 95% CI: 10.7–18.9%) of the subjects were phenotyped as poor metabolizers. The frequency of poor metabolizers was higher (P=0.0002; ² test) among the Faroese than in other European populations (7.4%). Genotype analyses for the CYP2D6*3, *4, *6 and *9 alleles were performed using real-time polymerase chain reaction (PCR) (TaqMan, Foster City, CA, USA), and we found 14.6% (n = 45) (95% CI: 10.8–19.0%) with deficient CYP2D6 genes (*3/*4, *4/*4, *4/*6, *6/*6) in the Faroese population. The subjects were phenotyped for CYP2C19 with the use of mephenytoin and 10 subjects, i.e., 3.2% (95% CI: 1.6–5.9%) were phenotyped as poor metabolizers. Genotype analysis for the CYP2C19*2 and *3 alleles was performed by means of PCR analysis, and 2.9% (n=9) (95% CI: 1.3–5.4%) of the Faroese were found to have a deficient CYP2C19 gene all explained by the CYP2C19*2/*2 genotype. The allele frequencies of the CYP2C9*2 and CYP2C9*3 alleles were 8.8% (95% CI: 6.7–11.4%) and 5.3% (95% CI: 3.7–7.4%), respectively, while the CYP2C8*3 allele frequency was 6.9% (95% CI: 5.0–9.2%). Real-time PCR (TaqMan) was used for both CYP2C9 and CYP2C8 genotype analyses.Conclusion The frequency of CYP2D6 poor metabolizers is twofold higher among the Faroese population than other Caucasians, while the frequencies of Faroese subjects with decreased CYP2C19, CYP2C8 and CYP2C9 enzyme activity are the same as seen in other Caucasian populations. A possible consequence might be a higher incidence of side effects among Faroese patients taking pharmaceuticals that are CYP2D6 substrates.     

The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects

AIMS: Our aim was to investigate the effect of the CYP2C8 inhibitor trimethoprim on the pharmacokinetics and pharmacodynamics of the antidiabetic drug repaglinide, and to examine the influence of the former on the metabolism of the latter in vitro. METHODS: In a randomized, double-blind, crossover study with two phases, nine healthy volunteers took 160 mg trimethoprim or placebo orally twice daily for 3 days. On day 3, 1 h after the last dose of trimethoprim or placebo, they ingested a single 0.25 mg dose of repaglinide. Plasma repaglinide and blood glucose concentrations were measured for up to 7 h post-dose. In addition, the effect of trimethoprim on the metabolism of repaglinide by human liver microsomes was investigated. RESULTS: Trimethoprim raised the AUC(0, infinity ) and C(max) of repaglinide by 61% (range, 30-117%; P= 0.0008) and 41% (P = 0.005), respectively, and prolonged the t((1/2)) of repaglinide from 0.9 to 1.1 h (P = 0.001). Trimethoprim had no significant effect on the pharmacokinetics of its aromatic amine metabolite (M1), but decreased the M1 : repaglinide AUC(0, infinity ) ratio by 38% (P = 0.0005). No effect of trimethoprim on the blood glucose-lowering effect of repaglinide was detectable. In vitro, trimethoprim inhibited the metabolism of (220 nm) repaglinide in a concentration-dependent manner. CONCLUSIONS: Trimethoprim raised the plasma concentrations of repaglinide probably by inhibiting its CYP2C8-mediated biotransformation. Although the interaction did not significantly enhance the effect of repaglinide on blood glucose concentration at the drug doses used, the possibility of an increased risk of hypoglycaemia should be considered during concomitant use of trimethoprim and repaglinide in patients with diabetes.     

Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide

BACKGROUND AND AIMS: Gemfibrozil, and particularly its combination with itraconazole, greatly increases the area under the plasma concentration-time curve [AUC(0, infinity)] and response to the cytochrome P450 (CYP) 2C8 and 3A4 substrate repaglinide. In vitro, gemfibrozil is a more potent inhibitor of CYP2C9 than of CYP2C8. Our aim was to investigate the effects of the gemfibrozil-itraconazole combination on the pharmacokinetics and pharmacodynamics of another meglitinide analogue, nateglinide, which is metabolized by CYP2C9 and CYP3A4. METHODS: In a randomized crossover study with two phases, nine healthy subjects took 600 mg gemfibrozil and 100 mg itraconazole (first dose 200 mg) twice daily or placebo for 3 days. On day 3, they ingested a single 30-mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 12 h. RESULTS: During the gemfibrozil-itraconazole phase, the AUC(0, infinity) and C(max) of nateglinide were 47% (range 23-74%; P < 0.0001) and 30% (range - 8% to 104%; P = 0.0146) higher than during the placebo phase, respectively, but the t(max) and t1/2 of nateglinide remained unchanged. The combination of gemfibrozil and itraconazole had no effect on the formation of the M7 metabolite of nateglinide but impaired its elimination. The blood glucose response to nateglinide was not significantly changed by coadministration of gemfibrozil and itraconazole. CONCLUSIONS: The combination of gemfibrozil and itraconazole has only a limited influence on the pharmacokinetics of nateglinide. This is in marked contrast to the substantial effect of this combination on the pharmacokinetics of repaglinide. The findings suggest that in vivo gemfibrozil, probably due to its metabolites, is a much more potent inhibitor of CYP2C8 than of CYP2C9.     

Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects

AIMS: Case reports suggest that gemfobrozil can increase the anticoagulant effect of warfarin. Because gemfibrozil inhibits CYP2C9 in vitro, we studied its effects on the pharmacokinetics and pharmacodynamics of racemic warfarin. METHODS: In a randomized cross-over study, 10 healthy subjects ingested 600 mg gemfibrozil or placebo twice daily for 8 days. On day 3, they were administered a single dose of 10 mg racemic R-S-warfarin orally. The concentrations of R- and S-warfarin in plasma and thromboplastin time were monitored up to 168 h. RESULTS: Gemfibrozil decreased the mean (+/-SD) area under the plasma concentration-time curve [AUC((0-infinity))] of S-warfarin by 11%, from 19.9 +/- 5.2 mg l(-1) h to 17.6 +/- 4.7 mg l(-1) h (95% CI on the difference -3.7, -0.78; P < 0.01) and that of R-warfarin by 6% from 31.3 +/- 7.5 mg l(-1) h during the gemfibrozil phase to 29.5 +/- 6.9 mg l(-1) h during the placebo phase (95% CI -3.3, -0.33; P < 0.05). There were no significant differences in the elimination half-lives of S- or R-warfarin between the phases. Gemfibrozil did not alter the anticoagulant effect of warfarin. CONCLUSION: Unexpectedly, gemfibrozil slightly decreased the plasma concentrations of R- and S-warfarin. Displacement of warfarin from plasma albumin by gemfibrozil or its interference with the absorption of warfarin could explain the present findings. Usual therapeutic doses of gemfibrozil seem to have limited effects on the pharmacokinetics and pharmacodynamics of single dose warfarin in healthy subjects.     

The impact of CYP2C8 polymorphism and grapefruit juice on the pharmacokinetics of repaglinide

AIMS: The primary aim of the study was to investigate the possible effect of the CYP2C8*3 allele and of grapefruit juice on the pharmacokinetics of repaglinide. Furthermore, the impact of a single dose of grapefruit juice on the pharmacokinetics of repaglinide in relation to dose. METHODS: Thirty-six healthy male subjects, genotyped for CYP2C8*3 (11 genotyped as CYP2C8*1/*3, one as CYP2C8*3/*3 and 24 as CYP2C8*1/*1), participated in a randomized, cross-over trial. In the two phases, the subjects drank 300 mL water or 300 mL grapefruit juice, in randomized order, 2 h before administration of a single dose of either 0.25 mg or 2 mg repaglinide. RESULTS: Neither the mean AUC(0-infinity) (geometric mean ratio: 1.01; 95% CI: 0.93-1.1, P = 0.88) nor the mean C(max) (geometric mean ratio: 1.05; 95% CI: 0.94-1.2, P = 0.35) of repaglinide were statistically significantly different in the group carrying the CYP2C8*3 mutant allele compared with wild-types. Grapefruit juice caused a 19% decrease in the geometric mean ratio of the 3-hydroxyquinidine to quinidine ratio (difference: 0.81; 95% CI: 0.75-0.87, P < 0.0001), which was used as an index of CYP3A4 activity, and an increase in the mean AUC(0-infinity) of repaglinide (geometric mean ratio: 1.13; 95% CI: 1.04-1.2, P = 0.0048), but had no statistically significant effect on the t(1/2). There was no statistically significant difference in blood glucose concentration in subjects who had or had not ingested grapefruit juice. The effect was more pronounced at the low dose of repaglinide (0.25 mg) than at the therapeutic dose of 2 mg. CONCLUSIONS: The pharmacokinetics of repaglinide in subjects carrying the CYP2C8*3 mutant allele did not differ significantly from those in the wild-types. Grapefruit juice increased the bioavailability of repaglinide, suggesting significant intestinal elimination of the drug which was assumed to be primarily mediated by CYP3A4 in the gut.     

中国2型糖尿病人中CYP2C8、CYP2C9基因多态性

目的：查明CYP2C9、CYV2C8等抗糖尿病药物主要代谢酶的基因多态性在中国2型糖尿病（T2DM）A-群中的分布频率和分布特征。方法：运用多聚酶链反应．限制性长度多态性（PCR．RFLP）方法和变性高效液相色谱法（DHPLC）对222名中国T2DM患者进行了有功能意义的CYP2C8＊3、CYP2C8P404A和CYP2C9＊3,以及可能存在功能意义的CYP2C8IVs2（-5insertt）突变体等等位基因型检测,并计算了各等位基因的频率。结果：222名中国T2DM患者的CYP2C8基因中未检出CYP2C8＊3、P404A型,CYP2C8IVS2（-5insertt）和CYP2C9＊3等位基因的频率分别为43．0％、2．48％,二者突变等位基因在男、女性别分布中不存在差异（P〉0．05）,同时为CYP2C8IVS2（-5insertt）和CYP2C9＊1＊3基因的频率为6．3％,该联合突变基因型的分布也不存在性别差异（P〉0．05）。结论：中国T2DM患者中CYP2C9＊3的等位基因频率为2．48％;未检出CYP2C8。3和P404A型,CYP2C81VS2（-5insertt）突变体发生频率为43．0％,其是否影响CYV2C8的代谢活力有待于进-步研究。     

Effects of ginkgo leaf tablet on the pharmacokinetics of rosiglitazone in rats and its potential mechanism

ContextGinkgo leaf tablet (GLT), a traditional Chinese herbal formula, is often combined with rosiglitazone (ROS) for type 2 diabetes mellitus treatment. However, the drug-drug interaction between GLT and ROS remains unknown.ObjectiveTo investigate the effects of GLT on the pharmacokinetics of ROS and its potential mechanism.Materials and methodsThe pharmacokinetics of 10 mg/kg ROS with 100/200 mg/kg GLT as single-dose and 10-day multiple-dose administration were investigated in Sprague-Dawley rats. In vitro, the effects of GLT on the activity of CYP2C8 and CYP2C9 were determined in recombinant human yeast microsomes and rat liver microsomes with probe substrates.ResultsThe t_1/2 of ROS increased from 2.14 ± 0.38 (control) to 2.79 ± 0.37 (100 mg/kg) and 3.26 ± 1.08 h (200 mg/kg) in the single-dose GLT administration. The AUC_0-t (139.69 ± 45.46 vs. 84.58 ± 39.87 vs. 66.60 ± 15.90 h·μg/mL) and t_1/2 (2.75 ± 0.70 vs. 1.99 ± 0.44 vs. 1.68 ± 0.35 h) decreased significantly after multiple-dose GLT treatment. The IC₅₀ values of quercetin, kaempferol, and isorhamnetin, GLT main constituents, were 9.32, 7.67, and 11.90 μmol/L for CYP2C8, and 27.31, 7.57, and 4.59 μmol/L for CYP2C9. The multiple-dose GLT increased rat CYP2C8 activity by 44% and 88%, respectively.Discussion and conclusionsThe metabolism of ROS is attenuated in the single dose of GLT by inhibiting CYP2C8 and CYP2C9 activity, and accelerated after the multiple-dose GLT treatment via inducing CYP2C8 activity in rats, indicating that the clinical dose of ROS should be adjusted when co-administrated with GLT.     

Prediction of inter-individual variability on the pharmacokinetics of CYP2C8 substrates in human

Inter-individual variability in pharmacokinetics can lead to unexpected side effects and treatment failure, and is therefore an important factor in drug development. CYP2C8 is a major drug-metabolizing enzyme known to be involved in the metabolism of over 100 drugs. In this study, we predicted the inter-individual variability in AUC/Dose of CYP2C8 substrates in healthy volunteers using the Monte Carlo simulation. Inter-individual variability in the hepatic intrinsic clearance of CYP2C8 substrates (CL_int,h,2C8) was estimated from the inter-individual variability in pharmacokinetics of pioglitazone, which is a major CYP2C8 substrate. The coefficient of variation (CV) of CL_int,h,2C8 was estimated to be 40%. Using this value, the CVs of AUC/Dose of other major CYP2C8 substrates, rosiglitazone and amodiaquine, were predicted to validate the estimated CV of CL_int,h,2C8. As a result, the reported CVs of both substrates were within the 2.5–97.5 percentile range of the predicted CVs. Furthermore, the CVs of AUC/Dose of the CYP2C8 substrates loperamide and chloroquine, which are affected by renal clearance, were also successfully predicted. Combining this value with previously reported CVs of other CYPs, we were able to successfully predict the inter-individual variability in pharmacokinetics of various drugs in clinical.     

Effect of a traditional Chinese medicine Liu Wei Di Huang Wan on the activities of CYP2C19, CYP2D6 and CYP3A4 in healthy volunteers

1. Liu Wei Di Huang Wan (LDW), a well-known traditional Chinese medicine, is widely used for the treatment of various diseases in China. This study was designed to investigate the potential herb–drug interactions of LDW in healthy volunteers and attempted to ascertain whether the interaction might be affected by genotypes.

2. We assessed the effect of LDW on the activities of CYP2C19, CYP2D6 and CYP3A4 in 12 Chinese healthy subjects in a single-center, controlled, non-blinded, two-way crossover clinical trial. The subject pool consisted of six extensive metabolizers with CYP2C19*1/*1 and six poor metabolizers with CYP2C19*2/*2. Placebo or 4.8?g LDW (12 pills, 0.2?g/pill, twice daily) was given to each participant for 14 continuous days with a wash-out period of 2 weeks after an oral administration of 30?mg omeprazole, 30?mg dextromethorphan hydrobromide and 7.5?mg midazolam. The activities of CYP2C19, CYP2D6 and CYP3A4 were ascertained by their respective plasma or urinary metabolic ratios on day 14 post-treatment.

3. There is no difference in the activities of the three tested enzymes before or after a 14-day administration of LDW. LDW had no effect on the pharmacokinetic parameters of the substrates and their metabolites.

4. A 14-day administration of LDW did not affect the activities of CYP2C19, CYP2D6 and CYP3A4. LDW is unlikely to cause pharmacokinetic interaction when it is combined with other medications predominantly metabolized by these enzymes.

     

The CYP2C8 inhibitor gemfibrozil does not increase the plasma concentrations of zopiclone

Objective Zopiclone is a short acting hypnotic, which is metabolised by cytochrome P450 (CYP) 3A4 and 2C8 in vitro. We studied the possible effect of gemfibrozil, an inhibitor of CYP2C8, on the pharmacokinetics and pharmacodynamics of zopiclone.Methods In a randomised 2-phase crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 3 days. On day 3, each ingested a 7.5 mg dose of zopiclone. Plasma concentrations and urinary excretion of zopiclone and its two primary metabolites, plasma gemfibrozil, and psychomotor performance were measured. The effects of CYP2C8, CYP2C9 and CYP3A4 inhibitors on the depletion of zopiclone (500 nM) were studied in vitro in human liver microsomes.Results The pharmacokinetic variables of the parent zopiclone were not significantly affected by gemfibrozil. However, gemfibrozil raised the mean peak plasma concentration (C_max) of N-oxide-zopiclone (1.6-fold; P<0.001) and that of N-desmethyl-zopiclone (1.2-fold; P<0.001). The mean area under the plasma concentration-time curve () values of N-oxide-zopiclone and N-desmethyl-zopiclone were raised 2-fold (P<0.001) and 1.2-fold (P<0.01), respectively. The renal clearance of N-oxide-zopiclone was reduced by 48% by gemfibrozil (P<0.001). The pharmacodynamic effects of zopiclone, measured using psychometric tests, were not affected by gemfibrozil. In vitro, ketoconazole (1 μM) and itraconazole (8 μM) decreased the elimination rate of zopiclone enantiomers by about 65–95%, while montelukast (16 μM), gemfibrozil (200 μM) and sulfaphenazole (10 μM) had no appreciable effect.Conclusions Gemfibrozil does not increase the plasma concentrations of the parent zopiclone. Accordingly, CYP2C8 does not significantly metabolise zopiclone in vivo. However, as gemfibrozil raises the concentrations of two potentially active metabolites of zopiclone, slightly enhanced effects of zopiclone by gemfibrozil can not be excluded.     

Effect of quercetin on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in healthy subjects

Previous in vitro studies have demonstrated that quercetin inhibits CYP2C8, but there are no available data to indicate that quercetin inhibits CYP2C8 in vivo. The effect of long-term use of quercetin on the pharmacokinetics of rosiglitazone was evaluated. After administration of quercetin or matched placebo for 3 weeks in a crossover manner, rosiglitazone 4 mg was administered, and the pharmacokinetics of rosiglitazone and N-desmethylrosiglitazone were determined. For AUCinfinity, AUClast, and Cmax, the geometric mean ratios (90% confidence interval) for (quercetin + rosiglitazone/placebo + rosiglitazone) were 0.98 (0.92, 1.05), 0.99 (0.92, 1.05), and 1.01 (0.88, 1.14), respectively. Metabolic conversion based on the AUC ratio of N-desmethylrosiglitazone/rosiglitazone in the quercetin phase (0.49 +/- 0.17) was similar to that of the placebo phase (0.47 +/- 0.14) (P = .574). Even though the acute interaction that would occur during the first few days of concurrent administration of quercetin cannot be excluded, these results indicate that long-term use of quercetin does not inhibit CYP2C8 activity, and the usage has little possibility of interacting with drugs that are metabolized by CYP2C8, including rosiglitazone.     

Stereoselective interaction between the CYP2C8 inhibitor gemfibrozil and racemic ibuprofen

Objective Ibuprofen, a nonsteroidal anti-inflammatory agent, is metabolised in vitro by cytochrome P450 (CYP) 2C8 and 2C9. We studied the possible effect of gemfibrozil, an in vivo inhibitor of CYP2C8, on the pharmacokinetics of ibuprofen in healthy volunteers. Methods In a randomised two-phase crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 3 days. On day 3, each subject ingested 400 mg of racemic ibuprofen. Plasma concentrations of ibuprofen enantiomers and gemfibrozil were measured. Results Gemfibrozil raised the mean total area under the plasma concentration-time curve (AUC_0–∞) of R-ibuprofen by 34% (range −10 to 67%; P < 0.001). The elimination half-lives (t _1/2) of R- and S-ibuprofen were increased by 54 and 34% (range 11–162% and 16–85%; P < 0.001) respectively. The other pharmacokinetic variables of R- and S-ibuprofen were not changed significantly. The AUC_0–∞ ratio of R-ibuprofen to S-ibuprofen was increased by gemfibrozil (P < 0.001). Conclusions Gemfibrozil moderately increases the AUC_0–∞ of R-ibuprofen and prolongs its t _1/2, indicating that R-ibuprofen is partially metabolised by CYP2C8. The interconversion of R- to S-ibuprofen can explain the small effect of gemfibrozil on the t _1/2 of S-ibuprofen. The gemfibrozil-ibuprofen interaction is of limited clinical significance.     

Identification of putative substrates for cynomolgus monkey cytochrome P450 2C8 by substrate depletion assays with 22 human P450 substrates and inhibitors

Cynomolgus monkeys are widely used in drug developmental stages as non‐human primate models. Previous studies used 89 compounds to investigate species differences associated with cytochrome P450 (P450 or CYP) function that reported monkey specific CYP2C76 cleared 19 chemicals, and homologous CYP2C9 and CYP2C19 metabolized 17 and 30 human CYP2C9 and/or CYP2C19 substrates/inhibitors, respectively. In the present study, 22 compounds selected from viewpoints of global drug interaction guidances and guidelines were further evaluated to seek potential substrates for monkey CYP2C8, which is highly homologous to human CYP2C8 (92%). Amodiaquine, montelukast, quercetin and rosiglitazone, known as substrates or competitive inhibitors of human CYP2C8, were metabolically depleted by recombinant monkey CYP2C8 at relatively high rates. Taken together with our reported findings of the slow eliminations of amodiaquine and montelukast by monkey CYP2C9, CYP2C19 and CYP2C76, the present results suggest that these at least four chemicals may be good marker substrates for monkey CYP2C8. Copyright © 2016 John Wiley & Sons, Ltd.     

The impact of the CYP2D6 and CYP2C19 genotypes on venlafaxine pharmacokinetics in a Japanese population

Objective: The cytochrome P ₄₅₀ isozymes CYP2D6 and CYP2C19 exhibit genetic polymorphism in human, including a marked interethnic difference. As the functional status of the isozymes CYP2D6 and CYP2C19 have an impact on the pharmacokinetics of some antidepressants, we investigated whether the disposition of venlafaxine was affected by the CYP2D6 and CYP2C19 genotypes. Methods: Twenty-eight adult Japanese men in good health participated in this study. Genomic DNA was isolated from peripheral lymphocytes, and the CYP2D6 genotype was determined using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) analysis and XbaI-RFLP analysis. Subjects were categorized into the following four groups: group 1 CYP2D6*10/*10; group 2 CYP2D6*1/*10 and *2/*10; group 3 CYP2D6*1/*1, *1/*2 and *2/*2; and group 4 the other genotypes. Two defective CYP2C19 alleles (CYP2C19*2 and CYP2C19*3) were identified by means of PCR-RFLP analysis. Venlafaxine was administered orally following an overnight fast. Plasma concentrations of venlafaxine and O-desmethylvenlafaxine were monitored using high-performance liquid chromatography up to 24 h. Results: The peak plasma concentration and values of area under the concentration–time curve up to 24 h for venlafaxine were 298% and 453% higher for group 1 than group 3, and 91% and 120% higher for group 2 than for group 3, respectively. The homozygote for two defective alleles of CYP2C19 showed a higher concentration of venlafaxine within group 1 and group 2. Conclusion: The CYP2D6*10 allele and two CYP2C19 defective alleles, common in an Asian population, are the most likely genetic factors to use in determining interindividual differences in the pharmacokinetics of venlafaxine, although the results with respect to CYP2C19 are preliminary because of the few subjects used. Received: 6 July 1999 / Accepted in revised form 11 January 2000     

Effect of a selective CYP2C9 inhibitor on the pharmacokinetics of nateglinide in healthy subjects

Purpose The objective of the study was to determine the effect of a potent and selective CYP2C9 inhibitor, sulfinpyrazone (Anturane), on the pharmacokinetics of nateglinide (Starlix), a novel antidiabetic drug which is primarily (~70%) metabolized via CYP2C9.Methods This was a randomized, open-label, two-period, crossover study in 18 healthy volunteers. Nateglinide was administered as a single 120-mg oral dose alone (reference) on day 1 or in combination with sulfinpyrazone (test) on day 7, following twice-daily 200-mg oral doses (i.e., 400 mg/day) of sulfinpyrazone for 7 days. Pharmacokinetic parameters of nateglinide were determined following the administration of nateglinide alone, and when administered in combination with sulfinpyrazone. Plasma nateglinide concentrations were determined using a validated high-performance liquid chromatography method.Results The administration of nateglinide in combination with sulfinpyrazone resulted in ~28% higher mean AUC of nateglinide (90% CI for test-reference ratio: 1.20–1.39) with no differences in mean peak plasma concentration (C_max; 90% CI test-reference ratio: 0.86–1.12) compared with nateglinide-alone treatment. The time to reach C_max (t_max) and the elimination half-life of nateglinide were similar between the two treatments. Both treatments were safe and well tolerated.Conclusions Sulfinpyrazone increased the mean exposure of nateglinide by 28% when both drugs were administered in combination. Nateglinide, given as a single dose or co-administered with multiple doses of sulfinpyrazone, was safe and well tolerated in healthy subjects.