Influence of CYP2C8 and CYP2C9 polymorphisms on pharmacokinetic and pharmacodynamic parameters of racemic and enantiomeric forms of ibuprofen in healthy volunteers

López‐Rodríguez, Rosario; Novalbos, Jesús; Gallego-Sandı́n, Sonia; Román-Martínez, Manuel; Torrado, Juan J.; Gisbert, Javier P.; Abad‐Santos, Francisco

doi:10.1016/j.phrs.2008.07.004

Cited by 57 publications

(45 citation statements)

References 37 publications

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“…All patients were evaluated for CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C8*5, CYP2C9*2, and CYP2C9*3 by real-time polymerase chain reaction in a LightCycler 480 (Roche), as previously described (López-Rodríguez et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

“…The most frequent CYP2C8 variants are *2 (Ile269Phe), *3 (linked polymorphisms Arg139Lys and Lys399Arg), *4 (Ile264Met), and *5 (rare nonsynonymous polymorphic allele). CYP2C8*2, CYP2C8*3, and CYP2C8*4 were associated with reduced enzyme activity (Dai et al, 2001;Daily and Aquilante, 2009;Gao et al, 2010), although some studies have shown higher capacity to metabolize repaglinide, rosiglitazone, pioglitazone, and R-ibuprofen in CYP2C8*3 carriers (Niemi et al, 2003;Kirchheiner et al, 2006;Tornio et al, 2008;López-Rodríguez et al, 2008). Allelic frequencies were 80, 2, 11, 7, and 0% for CYP2C8*1, *2, *3, *4, and *5 in a Spanish population, respectively (López-Rodríguez et al, 2008).…”

Section: Introductionmentioning

confidence: 98%

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Evaluation of the Relationship between Sex, Polymorphisms in CYP2C8 and CYP2C9, and Pharmacokinetics of Angiotensin Receptor Blockers

et al. 2012

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Angiotensin II receptor blockers (ARBs) are used to treat hypertension. Most ARBs are metabolized by CYP2C9. The aim of this study is to evaluate the possible association between sex, polymorphisms in the CYP2C8 and CYP2C9 genes, and the pharmacokinetics of losartan, valsartan, candesartan, and telmisartan. The study population comprised 246 healthy volunteers from seven single-dose clinical trials: 64 from two candesartan studies, 43 from a telmisartan study, 36 from a losartan study, and 103 from three valsartan studies. DNA was extracted from blood samples and single-nucleotide polymorphisms in the CYP2C8 (CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C8*5) and CYP2C9 (CYP2C9*2, CYP2C9*3) genes were evaluated using real-time polymerase chain reaction. Sex only affected telmisartan pharmacokinetics, since women showed a higher telmisartan C max than men (590.5 6 75.8 ng/ml versus 282.1 6 30.8 ng/ml; P £ 0.01). CYP2C9 variants were associated only with losartan pharmacokinetics: the half-life of losartan was higher in CYP2C9*3 allele carriers (3.1 6 0.4 hours) than in volunteers with the wild-type genotype (2.3 6 0.1 hours) (P £ 0.05). CYP2C8 polymorphisms were associated only with valsartan pharmacokinetics, since *2 allele carriers showed faster clearance (1.07 6 0.57 l/h·kg) than those with the wild-type genotype (0.48 6 0.72 l/h·kg; P £ 0.01) and carriers of the *3 allele (0.35 6 0.49 l/h·kg; P £ 0.001). These results suggest that genotypes for CYP2C9 and CYP2C8 are relevant to the pharmacokinetics of losartan and valsartan, respectively, but not the pharmacokinetics of candesartan or telmisartan.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Evaluation of the Relationship between Sex, Polymorphisms in CYP2C8 and CYP2C9, and Pharmacokinetics of Angiotensin Receptor Blockers

et al. 2012

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“…These authors also suggested that due to a strong linkage disequilibrium between these variants, it would be difficult to distinguish between associations with CYP2C8 or CYP2C9. Although the metabolism of most NSAIDs is associated with CYP2C9, CYP2C8 variants may also define interindividual differences in the pharmacokinetics of some NSAIDs, including ibuprofen and diclofenac (42,43).…”

Section: Cyp2c8mentioning

confidence: 99%

“…Several investigations tested if the CYP2C9 *2, *3, and CYP2C8*3 allelic variants could reduce ibuprofen metabolism and/or clearance (40,42,52), predisposing the carriers of both allelic variants to a higher risk of adverse drug reaction.…”

Section: The Relationship Between the Cyp2c9 Genotype And The Pharmacmentioning

confidence: 99%

“…López-Rodríguez et al (42) studied the effects of the CYP2C9 variants on the metabolism of both ibuprofen enantiomers in healthy volunteers and found lower metabolism of racemic ibuprofen in the 2C9*3 variant carriers, resulting in significantly higher area under the curve (AUC) and lower clearance than in the 2C9*1 allele carriers (p<0.05). As for S-ibuprofen, the clearance was 45 % lower in the 2C9*3 allele carriers, AUC 87 % higher, and half-life 47 % longer than in the 2C9*1 allele carriers.…”

Section: The Relationship Between the Cyp2c9 Genotype And The Pharmacmentioning

confidence: 99%

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How polymorphisms of the cytochrome P450 genes affect ibuprofen and diclofenac metabolism and toxicity / Kako polimorfizmi gena citokroma P450 utječu na metabolizam i toksičnost ibuprofena i diklofenaka

Krasniqi

Dimovski

Domjanović

et al. 2016

Archives of Industrial Hygiene and Toxicology

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Interindividual variability in drug metabolism is an important cause of adverse drug reactions and variability in drug efficiency. Polymorphisms of cytochrome P450 (CYPs) genes have a significant effect on drug metabolism and toxicity. This review brings an update about how genetic polymorphisms of CYP2C8 and CYP2C9 enzymes affect the disposition and clinical outcomes of ibuprofen and diclofenac, two of the most common pain relievers. The most common side effects associated with the influence of CYP2C8*3 and CYP2C9*2*3 variants on ibuprofen and diclofenac pharmacokinetics are hepatotoxicity and gastrointestinal bleeding. CYP genotyping may therefore identify patients at increased risk of these adverse reactions, and these patients could have their doses adjusted or start receiving another NSAID that does not share the same metabolic pathways with ibuprofen or diclofenac. However, before genotyping is introduced into regular clinical practice, more research is needed to evaluate the effectiveness of this strategy in improving treatment with ibuprofen and diclofenac.

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The Pharmacokinetics of Ibuprofen in Humans and Animals

Jamali

Brocks

2015

Ibuprofen

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Influence of CYP2C8 and CYP2C9 polymorphisms on pharmacokinetic and pharmacodynamic parameters of racemic and enantiomeric forms of ibuprofen in healthy volunteers

Cited by 57 publications

References 37 publications

Evaluation of the Relationship between Sex, Polymorphisms in CYP2C8 and CYP2C9, and Pharmacokinetics of Angiotensin Receptor Blockers

Evaluation of the Relationship between Sex, Polymorphisms in CYP2C8 and CYP2C9, and Pharmacokinetics of Angiotensin Receptor Blockers

How polymorphisms of the cytochrome P450 genes affect ibuprofen and diclofenac metabolism and toxicity / Kako polimorfizmi gena citokroma P450 utječu na metabolizam i toksičnost ibuprofena i diklofenaka

The Pharmacokinetics of Ibuprofen in Humans and Animals

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