CYP2C9 genetic variants and losartan oxidation in a Turkish population

Babaoğlu, Melih O.; Yaşar, Ümit; Sandberg, Mia; Eliasson, Erik; Dahl, Marja­‐Liisa; Kayaalp, S. O.; Bozkurt, Atilla

doi:10.1007/s00228-004-0785-5

Cited by 48 publications

(53 citation statements)

References 29 publications

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“…We did not observe differences in the pharmacokinetics of losartan according to the CYP2C8 polymorphism, possibly reflecting that no losartan metabolite was formed by CYP2C8 in vitro (Babaoglu et al, 2004).…”

Section: Discussionmentioning

confidence: 54%

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: Discussionmentioning

confidence: 54%

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

et al. 2012

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“…Tolbutamide, flurbiprofen, phenytoin and warfarin have been suggested as alternative probe agents for phenotyping purpose [19]. Recently, urinary losartan/ E3174 ratio after an oral dose of losartan has also been suggested as a safe and selective measure of CYP2C9 activity in Turkish patients, as well as in various studies performed in Beninese, Japanese, Spanish and Swedish populations [5,6,14,20,21]. In the present study, we used a single subtherapeutic dose of losartan as a probe for determination of CYP2C9 activity; no side effect was reported by the patients.…”

Section: Discussionmentioning

confidence: 99%

“…Analysis of losartan and its carboxy metabolite, E3174, in urine was performed by high pressure liquid chromatography (HPLC) system with a fluorescence detection as described previously [14]. In brief, urine samples were mixed with 0.5 M citrate buffer and isopropanol (4/1/1:v/v/v, respectively) to yield a pH of 4.3.…”

Section: Methodsmentioning

confidence: 99%

Inhibitory Effect of Valproic Acid on Cytochrome P450 2C9 Activity in Epilepsy Patients

Gunes¹,

Bilir

Zengil³

et al. 2007

Basic Clin Pharma Tox

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Drug interactions constitute a major problem in the treatment of epilepsy because drug combinations are so common. Valproic acid is a widely used anticonvulsant drug with a broad therapeutic spectrum. Case reports suggest interaction between valproic acid and other drugs metabolized mainly by cytochrome P450 isoforms. The aim of this study was to evaluate the inhibitory effect of valproic acid on cytochrome P450 2C9 (CYP2C9) activity by using losartan oxidation as a probe in epilepsy patients. Patients were prescribed sodium valproate (mean 200 mg/day for the first week and 400 mg/day in the following period) according to their clinical need. A single oral dose of 25 mg losartan was given to patients before and after the first dose, first week and 4 weeks of valproic acid treatment. Losartan and E3174, the CYP2C9-derived carboxylic acid metabolite of losartan in 8 hr urine were assayed by using high pressure liquid chromatography. Urinary losartan/E3174 ratio did not change significantly on the first day (0.9, 0.3-3.5; median, range), and first week (0.6, 0.2-3.8; median, range), while a significant increase was observed after 4 weeks of valproic acid treatment (1.1, 0.3-5.7; median, range) as compared to that of measured before valproic acid administration (0.6, 0.1-2.1; median, range) (P = 0.039). The degree of inhibition was correlated with the steady-state plasma concentrations of valproic acid ( r 2 = 0.70, P = 0.04). The results suggest an inhibitory effect of valproic acid on CYP2C9 enzyme activity in epilepsy patients at steady state. The risk of pharmacokinetic drug-drug interactions should be taken into account during concomitant use of valproic acid and CYP2C9 substrates.The high risk of drug-drug interactions in the treatment of epilepsy is generally attributed to the long-term treatment of the disease and common use of drug combinations. Valproic acid is a first-line drug for the treatment of primary generalized tonic-clonic, absence and partial seizures. It has also been used in the treatment of psychiatric disorders due to its modulator effect on serotoninergic and dopaminergic transmission [1].Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme that catalyses the major pathways in the metabolism of a large number of clinically used drugs such as phenytoin, oral anticoagulants, oral antidiabetics and nonsteroidal antiinflammatory drugs [2]. The CYP2C9*2 and CYP2C9*3 variants code for enzymes with decreased activity, compared to the enzyme coded by the common variant CYP2C9*1 allele [3]. Losartan, a selective angiotensin II receptor antagonist, is converted to its active metabolite, E3174, by CYP2C9 [4]. Urinary losartan/E3174 ratio after a single oral dose of losartan (25 mg) has been suggested as a useful marker for measuring CYP2C9 activity in human beings [5,6]. Although the cytochrome P450 enzymes do not catalyse the major metabolic pathway for valproic acid, it has been shown that CYP2C9 and CYP2A6 catalyse the formation of its hepatotoxic metabolite 4-ene-valproic acid [7]. Additi...

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“…However, losartan is oxidized primarily by CYP2C9 to an active carboxylic acid metabolite, E-3174, which has higher potency and a longer half-life than losartan and is therefore responsible for most of the antihypertensive effects (14,15). The effects of CYP2C9*2 and CYP2C9*3 on losartan oxidation have been extensively studied both in vitro and in vivo, consistently demonstrating the functional defect of the CYP2C9*3 allele in decreasing the oxidation of losartan (16)(17)(18)(19)(20). However, the clinical relevance of genotypes of CYP2C9 to the variable blood pressure-lowering responses to losartan in hypertensive patients has not been fully clarified.…”

Section: Genetic Variations Of Cyp2c9 In 724 Japanese Individuals Andmentioning

confidence: 99%

Genetic Variations of CYP2C9 in 724 Japanese Individuals and Their Impact on the Antihypertensive Effects of Losartan

et al. 2008

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CYP2C9 genetic variants and losartan oxidation in a Turkish population

Cited by 48 publications

References 29 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

Inhibitory Effect of Valproic Acid on Cytochrome P450 2C9 Activity in Epilepsy Patients

Genetic Variations of CYP2C9 in 724 Japanese Individuals and Their Impact on the Antihypertensive Effects of Losartan

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