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- Itkonen, Matti K., et al.
(författare)
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Clopidogrel but Not Prasugrel Significantly Inhibits the CYP2C8-Mediated Metabolism of Montelukast in Humans
- 2018
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Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 104:3, s. 495-504
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Tidskriftsartikel (refereegranskat)abstract
- The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y(12) inhibitors on montelukast pharmacokinetics. Clopidogrel (300mg on day 1 and 75mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P < 0.001) and decreased the M6:montelukast AUC(0-7h) ratio to 45% of control (90% CI 40-50%, P < 0.001). Prasugrel (60mg on day 1 and 10mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.
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| 2. |
- Fanta, Samuel, et al.
(författare)
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Pharmacogenetics of cyclosporine in children suggests an age-dependent influence of ABCB1 polymorphisms
- 2008
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Ingår i: Pharmacogenetics and genomics. - 1744-6872. ; 18:2, s. 77-90
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate whether variations in the ABCB1, ABCC2, SLCO1B1, CYP3A4, CYP3A5, or NR1I2 genes are associated with the pharmacokinetics of cyclosporine in pediatric renal transplant candidates, and whether the effects of these variants are related to age. METHODS: A total of 104 pediatric patients (aged 0.36-16.3 years) were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. The patients had undergone a pharmacokinetic study with intravenous and oral ciclosporine (INN, cyclosporin) before renal transplantation. RESULTS: In the whole population, the mean+/-SD cyclosporine oral bioavailability was 0.38+/-0.09, volume of distribution was 2.3+/-0.54 l/kg, and systemic clearance normalized by allometric body weight was 0.88+/-0.16 l/h/kg3/4. The prehepatic extraction ratio was 0.51+/-0.13, and the hepatic extraction ratio was 0.24+/-0.04, the former explaining 95% of the variability in oral bioavailability (P<0.0001). In children older than 8 years, the pre-hepatic extraction was 0.64+/-0.09 in those with the ABCB1 c.2677GG genotype, 0.52+/-0.11 in those with the c.2677GT genotype, and 0.41+/-0.03 in those with the c.2677TT genotype (P=0.021, r2=0.334), leading to corresponding differences in oral bioavailability (0.28+/-0.07, 0.36+/-0.07, and 0.44+/-0.04, respectively; P=0.012, r2=0.372). Similar associations were observed with the ABCB1 c.1236C>T variant and the related haplotype c.1199G-c.1236C-c.2677G-c.3435C (P<0.05). The estimated oral dose requirement and clearance of cyclosporine remained largely unexplained by the genetic variations. CONCLUSIONS: Although these data suggest an age-related effect of ABCB1 polymorphism on oral bioavailability, further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.
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