SLCO2B1 c.935G>A single nucleotide polymorphism has no effect on the pharmacokinetics of montelukast and aliskiren.

OBJECTIVE: A nonsynonymous single nucleotide polymorphism (SNP) in the SLCO2B1 gene encoding organic anion transporting polypeptide 2B1 (OATP2B1), c.935G>A (p.R312Q; rs12422149), has been associated with reduced plasma concentrations of montelukast in patients with asthma. Our aim was to examine the possible effects of the SLCO2B1 c.935G>A SNP on the single-dose pharmacokinetics of the suggested OATP2B1 substrates montelukast and aliskiren. METHODS: Sixteen healthy volunteers with the SLCO2B1 c.935GG genotype, 12 with the c.935GA genotype, and five with the c.935AA genotype ingested a single 10 mg dose of montelukast or a 150 mg dose of aliskiren, with a washout period of 1 week. Plasma montelukast concentrations were measured up to 24 h. Plasma and urine aliskiren concentrations were measured up to 72 and 12 h, respectively, and plasma renin activity up to 24 h after aliskiren intake. RESULTS: The SLCO2B1 genotypes had no significant effect on the pharmacokinetics of montelukast or aliskiren. The geometric mean ratios with 90% confidence intervals of montelukast area under the plasma concentration-time curve from 0 h to infinity (AUC(0-∞)) in participants with the c.935GA or the c.935AA genotype to those with the c.935GG genotype were 1.02 (0.87, 1.21) or 0.88 (0.71, 1.10), respectively (P=0.557). The geometric mean ratios (90% confidence interval) of aliskiren AUC(0-∞) in participants with the c.935GA or the c.935AA genotype to those with the c.935GG genotype were 0.98 (0.74, 1.30) or 1.24 (0.85, 1.80), respectively (P=0.576). CONCLUSION: These data do not support the suggested functional significance of the SLCO2B1 c.935G>A SNP on OATP2B1 activity in vivo.

Fluconazole but not the CYP3A4 inhibitor, itraconazole, increases zafirlukast plasma concentrations.

PURPOSE: Zafirlukast is a substrate of cytochrome P450 2C9 (CYP2C9) and cytochrome P450 3A4 (CYP3A4) in vitro, but the role of these enzymes in its metabolism in vivo is unknown. To investigate the contribution of CYP2C9 and CYP3A4 to zafirlukast metabolism, we studied the effects of fluconazole and itraconazole on its pharmacokinetics (PK). METHODS: In a randomized crossover study, 12 healthy volunteers ingested fluconazole 200 mg (first dose 400 mg) once daily, itraconazole 100 mg (first dose 200 mg) twice daily, or placebo twice daily for 5 days, and on day 3, 20 mg zafirlukast. Plasma concentrations of zafirlukast and the antimycotics were measured up to 72 h. RESULTS: Fluconazole increased the total area under the plasma concentration-time curve (AUC) of zafirlukast 1.6-fold [95% confidence interval (CI) 1.3-2.0-fold, P < 0.001), and its peak plasma concentration 1.5-fold (95% CI 1.2-2.0-fold, P < 0.05). Fluconazole did not affect the time of peak plasma concentration or elimination half-life of zafirlukast. None of the zafirlukast PK variables differed significantly from the control in the itraconazole phase; e.g., the ratio to control of the total AUC of zafirlukast was 1.0 (95% CI 0.82-1.2) during the itraconazole phase. CONCLUSIONS: Fluconazole, but not itraconazole, increases zafirlukast plasma concentrations, strongly suggesting that CYP2C9 but not CYP3A4 participates in zafirlukast metabolism in humans.

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 CYP2C8 inhibitor gemfibrozil does not affect the pharmacokinetics of zafirlukast.

PURPOSE: Gemfibrozil, a strong inhibitor of cytochrome P450 (CYP) 2C8 in vivo, was recently found to markedly increase the plasma concentrations of montelukast in humans. Like montelukast, zafirlukast is a substrate of CYP2C9 and CYP3A4 and a potent inhibitor of CYP2C8 in vitro. To investigate the contribution of CYP2C8 to the metabolism of zafirlukast in vivo, we studied the effect of gemfibrozil on the pharmacokinetics of zafirlukast. METHODS: Ten healthy subjects in a randomized cross-over study took gemfibrozil 600 mg or placebo twice daily for 5 days, and on day 3, a single oral dose of 20 mg zafirlukast. The plasma concentrations of zafirlukast were measured for 72 h postdose. RESULTS: The mean total area under the plasma concentration-time curve of zafirlukast during the gemfibrozil phase was 102% (geometric mean ratio; 95% confidence interval 89-116%) of that during the placebo phase. Furthermore, there were no statistically significant differences in the peak plasma concentration, time of peak concentration, or elimination half-life of zafirlukast between the phases. CONCLUSIONS: Gemfibrozil has no effect on the pharmacokinetics of zafirlukast, indicating that CYP2C8 does not play a significant role in the elimination of zafirlukast.