Active Metabolite E-3174 Research Articles

A Method for Assay of Losartan, Its Active Metabolite E-3174, and Glibenclamide in Human Serum and Urine by HPLC-MS/MS

A Method for Assay of Losartan, Its Active Metabolite E-3174, and Glibenclamide in Human Serum and Urine by HPLC-MS/MS

Influence of CYP2C9 Genetic Polymorphisms on the Pharmacokinetics of Losartan and Its Active Metabolite E-3174: A Systematic Review and Meta-Analysis

This study aimed to investigate the influence of CYP2C9 genetic polymorphisms on the pharmacokinetics of losartan and its active metabolite, E-3174, through a systematic review and meta-analysis. Eight studies published before March 2021 were included in this study. We used PubMed, the Cochrane Library, EMBASE, and Web of Science, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The data analysis was conducted through Review Manager (RevMan), version 5.3, and R software. We found that healthy volunteers with CYP2C9*2 or *3 carriers had higher area under the curve (AUC0-∞) of losartan (mean difference (MD) 0.17 ; 95% confidence intervals (CI): 0.04, 0.29) and lower AUC0-∞ of E-3174 (MD −0.35 ; 95% CI: −0.62, −0.08) than those with CYP2C9*1/*1. Subjects with CYP2C9*2 or *3 carriers showed lower maximum concentration (Cmax) of E-3174 than those with CYP2C9*1/*1 (MD −0.13 ; 95% CI: −0.17, −0.09). For half-life, subjects with CYP2C9*2 or *3 carriers had longer half-lives of losartan and E-3174 than those with CYP2C9*1/*1 (MD 0.47 h; 95% CI: 0.32, 0.61 and MD 0.68 h; 95% CI: 0.44, 0.92, respectively). This meta-analysis suggests that the pharmacokinetics of losartan and E-3174 are associated with the CYP2C9 polymorphisms

Effect of CYP2C9 genetic polymorphism and breviscapine on losartan pharmacokinetics in healthy subjects

1. Breviscapine was an active ingredient of flavonoid glycosides. Our present study was conducted to evaluate the impact of breviscapine on the pharmacokinetics of losartan and its active metabolite E-3174, and that relationship with the gene polymorphism of CYP2C9 in healthy Chinese volunteers, to provide a basis for clinical rational drug use. 2. The genotypes of 217 healthy Chinese subjects were determined using PCR-RFLP. Twelve healthy subjects were selected and were known CYP2C9 genotypes (six CYP2C9*1/*3 and six CYP2C9*1/*1) in a two-phase randomised crossover design study. These subjects were given daily doses of 120 mg (40 mg, three times a day) of breviscapine or a placebo for 14 days, followed by 50 mg losartan on day 15. 3. Compared with individuals carrying the CYP2C9*1/*1 genotype, the CYP2C9*1/*3 genotype showed an increase in the AUC(0–36) (833.6 ± 379.8 ng h ml−1 vs. 526.1 ± 140.1 ng h ml−1, p < 0.05) and a decrease in the MR (the metabolic ratio of losartan, AUCE-3174/AUClosartan) (2.67 ± 1.40 vs. 4.56 ± 0.83, p < 0.05) of losartan during the placebo treatment phase. Individuals with genotype CYP2C9*1/*3 showed a significant increase in AUC(0–36) (2335 ± 851.8 ng h ml−1 vs. 1927 ± 949.5 ng h ml−1, p < 0.05) and AUC(0–∞) (2363 ± 875.6 ng h ml−1 vs. 1966 ± 966.1 ng h ml−1, p < 0.05) of E-3174 after breviscapine treatment compared to the placebo group. 4. In healthy subjects, breviscapine had no significant effect on the pharmacokinetics of losartan. The activity of CYP2C9 enzyme to losartan metabolism was more significant in subjects with CYP2C9*1/*3 than those with CYP2C9*1/*1 genotype.

Influence of CYP2C9*2 genetic polymorphism on pharmacokinetics of losartan and its active metabolite E-3174 on the background of CYP3A4 wild genotype in healthy Chinese Hui subjects

In the present study,we aimed to investigate the influence of CYP2C9*2 genetic polymorphism on pharmacokinetics of losartan and its active metabolite E-3174 on the background of CYP3A4 wild genotype in healthy Chinese Hui subjects.Blood samples were collected from subjects for CYP2C9 and CYP3A4 genotyping using a polymerase chain reaction-restriction fragment length polymorphism（PCR-RFLP） assay.A pharmacokinetic study was then carried out in two groups with CYP2 C9*1/*1（n = 8） and CYP2 C9*1/*2（n = 6） genotypes at the same time,and all the 14 subjects were CYP3A4 wild genotype.Plasma levels of losartan and E-3174 were determined by high-performance liquid chromatography-fluorescence（HPLC-FLD） method before and after a single oral dose of 50-mg dose of losartan in tablet form.The pharmacokinetic parameters were calculated by DAS 2.0 software and analyzed by SPSS 16.0 software.Pharmacokinetic parameters,including area under the curve from 0 h to the last measured point 24 h(AUC0–24),area under the curve from 0 h to infinite time(AUC0–∞),peak plasma concentration（Cmax）,time to reach Cmax（tmax）,oral clearance（CL）,oral volume of distribution（Vd） and elimination half-life(t1/2),were determined.Compared with the CYP2C9*1/*2 group,the AUC0–24,AUC0–∞ and Cmax of E-3174 in CYP2C9*1/*1 group of Hui subjects were respectively 1.36,1.32 and 1.64 times more,and the statistic differences were significant（P<0.05）.The CYP2C9*2 mutant allele played an important role in the pharmacokinetics of losartan after oral administration,and it might decrease the generation of E-3174.However,large-sample clinical trials are required to validate whether the dose adjustment according to CYP2C9 genotype is necessary.

Population pharmacokinetic of losartan and its active metabolite E-3174 in five different ethnic populations of China

Population pharmacokinetic of losartan and its active metabolite E-3174 in five different ethnic populations of China

Effects of CYP2C9*1/*3 and *1/*13 on the pharmacokinetics of losartan and its active metabolite E-3174

The effects of CYP2C9*1/*3 and *1/*13 genotypes were evaluated on the pharmacokinetics of losartan and its active metabolite, E-3174, in Korean subjects. Losartan (50 mg) was administered in 43 Korean volunteers with different CYP2C9 genotypes (CYP2C9*1/*1, *1/*3 and *1/*13). Losartan and E-3174 levels in the plasma and urine were analyzed by HPLC using fluorescence. The CYP2C9*1/*13 subjects showed lower oral clearance (p < 0.001) and greater AUC0-∞ (p < 0.01) of losartan and higher Cmax (p < 0.01) and longer half-life (p < 0.001) of E-3174 than the CYP2C9*1/*1 subjects, but AUC0-∞ of E-3174 was not different. The CYP2C9*1/*3 subjects showed lower oral clearance (p < 0.001) of losartan and higher Cmax (p < 0.01) and longer half-life (p < 0.01) of E-3174 than the CYP2C9*1/*1 subjects. However, AUC0-∞ of losartan was greater in CYP2C9*1/*3 subjects than in CYP2C9*1/*1, but these results were not significant (p < 0.05, but statistical power < 0.8). In addition, AUC0-∞ of E-3174 was not different. There were no significant differences in pharmacokinetic parameters between the CYP2C9*1/*13 and CYP2C9*1/*3 subjects. These results suggest that CYP2C9*1/*3 and CYP2C9*1/*13 are similarly associated with decreased formation of E-3174 from losartan, but the clinical effects of losartan may not be reduced by CYP2C9*1/*3 and CYP2C9*1/*13.

Pharmacokinetics of Hydrochlorothiazide, Losartan and E3174 after Oral Doses of Losartan and Losartan/Hydrochlorothiazide in Healthy Chinese Male Volunteers

Aims: A simple and highly sensitive LC-MS method was used to determine the concentrations of losartan, its major active metabolite E3174 and hydrochlorothiazide in human plasma and pharmacokinetic characteristics and metabolism phenotype observation after administration of losartan tablets and losartan/hydrochlorothiazide combination tablets. Methods: An open, randomized cross-over single-dose study was designed in forty healthy male volunteers, A single-dose of 50 mg losartan tablets or 50 mg losartan/12.5 mg hydrochlorothiazide combination tablets was orally given and blood samples were collected at scheduled time. A LC-MS method was established and evaluated for determining the plasma concentrations of losartan, E3174 and hydrochlorothiazide. The pharmacokinetic parameters and characteristic of metabolism phenotypes were calculated and compared via this test. Results: The elimination rate of E3174 (t1/2) was significantly shorter (P 0–t was lower (P 1/2, AUC0–t and AUC0–inf of E3174.

Losartan probe in healthy volunteer for assessment CYP2C9 activity: Russian experience

Event Abstract Back to Event Losartan probe in healthy volunteer for assessment CYP2C9 activity: Russian experience George S. Anikin1*, D A. Sychev1, I V. Ignatiev1, M A. Smirnova1, A Y. Savchenko1, A V. Dmitriev1 and G V. Ramenskaya1 1 Moscow Medical Sechenov Academy, 10th therapy department of City Clinical Hospital, Russia Introduction. Losartan is selective angiotensin receptor antagonist, is mainly metabolized by CYP2C9 to an active metabolite E3174, which is more potent inhibitor than the parent compound. Co-treatment both substrates and inhibitors of CYP2C9 is consider to increase of side effect risk of the first one. We applied losartan probe to clear the influence of different factors (cranberry juice and fluconasol) on losartan pharmacokinetics in healthy volunteers and to assess safety and effectiveness of this probe. Methods. In present study were included 20 healthy volunteers. Study was consist of 3 stages divided 7-days washout period. At the first stage (Los) volunteers took 50 mg of losartan under fasting condition. At the second stage (CJ), they took 50 mg of losartan with 250 ml of cranberry juice (35%). At night before third stage (Fluc) volunteers took 150 mg of fluconazol, next morning took 50 mg losartan. 8-hours urine portions were collected at the each stage of experiment for assessment losartan metabolic ratio (LMR) calculated as (losartan concentration) / (E-3174 concentration). The concentration of losartan and E-3174 were detected by liquid chromatography-mass spectrometry technique. Results. Significant differences were between Los – Fluc (p=0.028) and CJ – Fluc (p=0.022) LMR ratio. The cranberry juice in single dose (the most concentrated juice on offer) did not inhibit CYP2C9 (p=0.687). There was not significant decreasing blood pressure over the time of study. Discussion. The results of our study demonstrate evident inhibiting effect of fluconasol (CYP2C9 inhibitor) on losartan pharmacokinetics in comparison with Los (p=0.028) and CJ stages (p=0.022). Single dose (250 ml) of the most concentrated cranberry juice had no effect. Losartan probe evaluating CYP2C9 activity allows as taking into account both phenotypic and genotypic patient’s features and adjust individual dose (especially warfarin) as soon as possible. Keywords: Losartan, angiotensin receptor antagonist, CYP2C9 enzyme Conference: 8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010, Thessaloniki, Greece, 1 Oct - 5 Oct, 2010. Presentation Type: Oral Topic: Xenobiotic toxicity Citation: Anikin GS, Sychev DA, Ignatiev IV, Smirnova MA, Savchenko AY, Dmitriev AV and Ramenskaya GV (2010). Losartan probe in healthy volunteer for assessment CYP2C9 activity: Russian experience. Front. Pharmacol. Conference Abstract: 8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010. doi: 10.3389/conf.fphar.2010.60.00100 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 28 Oct 2010; Published Online: 04 Nov 2010. * Correspondence: Dr. George S Anikin, Moscow Medical Sechenov Academy, 10th therapy department of City Clinical Hospital, Moscow, Russia, medi123@rambler.ru Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers George S Anikin D A Sychev I V Ignatiev M A Smirnova A Y Savchenko A V Dmitriev G V Ramenskaya Google George S Anikin D A Sychev I V Ignatiev M A Smirnova A Y Savchenko A V Dmitriev G V Ramenskaya Google Scholar George S Anikin D A Sychev I V Ignatiev M A Smirnova A Y Savchenko A V Dmitriev G V Ramenskaya PubMed George S Anikin D A Sychev I V Ignatiev M A Smirnova A Y Savchenko A V Dmitriev G V Ramenskaya Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Development of swelling/floating gastroretentive drug delivery system based on a combination of hydroxyethyl cellulose and sodium carboxymethyl cellulose for Losartan and its clinical relevance in healthy volunteers with CYP2C9 polymorphism

The aim of this study was to develop an optimal gastroretentive drug delivery system (GRDDS) for administering Losartan. Additionally, the influence of optimized GRDDS on the bioavailability of Losartan and the formation extent of active metabolite E3174 by CYP2C9 polymorphism was investigated. Swellable and floatable GRDDS tablets combining hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose (NaCMC), and sodium bicarbonate were prepared at various compression pressures for evaluating swelling characteristics and floating capacity. Then Losartan was incorporated into optimized formulations for in vitro and in vivo characterizations. An appropriate ratio of HEC to NaCMC, addition of sodium bicarbonate, and compression at lower pressures resulted in the tablets floating over SGF for more than 16 h and swelling to 2 cm in diameter within 3 h. The release patterns of Losartan from these tablets were pH-dependent. Results of the clinical trials showed that the mean bioavailability from GRD-A (HEC 91.67%, sodium bicarbonate 3.33% and Losartan 8.33%) was approximately 164%, relative to the immediate-release product (Cozaar ®). MRT and t max values were greater and C max values were lower for the GRDDS tablets compared with Cozaar ®. The lower bioavailability of Losartan in the CYP2C9*1/*1 subjects than CYP2C9*1/*3 subjects was found and could be due to the variety of enzymatic activity.

Effect of silymarin on the pharmacokinetics of losartan and its active metabolite E-3174 in healthy Chinese volunteers

To investigate the effects of silymarin on the pharmacokinetics of losartan and its active metabolite E-3174 and its relationship with CYP2C9 genotypes. Twelve healthy adult men of known CYP2C9 genotype (six CYP2C9*1/*1 and six CYP2C9*1/*3) were recruited in a two-phase randomized crossover design study. The pharmacokinetics of losartan and E-3174 were measured before and after a 14-day treatment with 140 mg of silymarin three times daily. The area under the plasma concentration-time curve (AUC) of losartan increased significantly following a 14-day silymarin treatment in subjects with the CYP2C9*1/*1 genotype, but not in those with the CYP2C9*1/*3 genotype. The AUC of E-3174 decreased significantly with a silymarin pretreatment in both CYP2C9*1/*1 and the CYP2C9*1/*3 subjects. The metabolic ratio of losartan (ratio of AUC(0-infinity) of E-3174 to AUC(0-infinity) of losartan) decreased significantly after a 14-day treatment with silymarin in individuals with the CYP2C9*1/*1 genotype (p < 0.05), but not in those with the CYP2C9*1/*3 genotype (p = 0.065). Silymarin inhibits the metabolism of losartan to E-3174, with the magnitude of the interaction differing in individuals with different CYP2C9 genotypes.

Pressure Promotes Angiotensin II–Mediated Migration of Human Coronary Smooth Muscle Cells Through Increase in Oxidative Stress

Angiotensin II--mediated oxidative stress may play a role in the pathogenesis of coronary atherosclerosis. We examined the effects of pressure on the angiotensin II--mediated increase in oxidative stress and migration of cultured human coronary smooth muscle cells (SMCs). Increased pressure (100 mm Hg) by helium gas for 48 hours increased angiotensin II--mediated oxidative stress as evaluated by flow cytometry and SMC migration (from 15.9 +/- 2.2 to 32.0 +/- 2.4 cells per 4 high-power fields, P<0.05; n=8). The pressure-induced increases in oxidative stress observed appear to involve phospholipase D (PLD) and protein kinase C (PKC), inasmuch as the indirect PLD inhibitor suramin, at 100 micromol/L, and the PKC inhibitor chelerythrine, at 1 micromol/L, completely blocked the increase in angiotensin II--mediated oxidative stress induced by pressure. Pressure-induced increase in angiotensin II--mediated oxidative stress was inhibited by diphenylene iodonium chloride, an NADPH oxidase inhibitor, by 79% (P<0.05, n=8). Losartan (1 micromol/L), its active metabolite E3174 (1 micromol/L), and the antioxidant N-acetylcysteine (100 mmol/L) but not PD123319 (1 micromol/L) also blocked pressure-induced increases in angiotensin II--mediated oxidative stress and SMC migration (P<0.05, n=8). These findings suggest a novel cellular mechanism whereby pressure regulates the angiotensin II--mediated migration of SMCs, possibly via angiotensin II type 1 receptors, and which involves PLD-mediated, PKC-mediated, and NADPH oxidase--mediated increases in oxidative stress.

A risk-benefit assessment of losartan potassium in the treatment of hypertension.

Losartan potassium is the first of a new class of orally active antihypertensive drugs which antagonise the action of angiotensin (AT) II at the AT1 receptor subtype. Losartan potassium is converted by the liver to the active metabolite E-3174, which is a more potent antagonist at the AT1 receptor. E-3174 is responsible for most of the pharmacological effects of losartan potassium, and its long half-life contributes to the extended duration of action of the drug. Losartan potassium is effective as a once-daily antihypertensive agent. In mild to moderate hypertension, losartan potassium has similar efficacy to enalapril, atenolol and felodipine extended release. When losartan potassium is combined with hydrochlorothiazide there is a further reduction in blood pressure. Losartan potassium is well tolerated in mild, moderate and severe essential hypertension, with dizziness being reported as the only drug-related adverse effect. The overall rate of patient withdrawal from therapy due to adverse experiences with losartan potassium is lower (2.3%) than that of placebo (3.7%). First-dose hypotension is uncommon, perhaps due to the slower onset of action of the drug, and cough does not appear to be a significant problem. A number of areas concerning the safety and efficacy of losartan potassium remain to be clarified. In particular, long term tolerability studies are needed; cough only became apparent as an adverse effect of ACE inhibitors after 3 to 4 years of use. Postmarketing surveillance has shown that angioedema, a rare but life-threatening adverse effect of ACE inhibitors, also occurs with losartan potassium. Further data are needed on the use of losartan potassium in patients with renal impairment before accepting the recommendation that dosage adjustment is not necessary. The pharmacokinetics and pharmacodynamics of losartan potassium in patients with hepatic disease also require further investigation. Losartan potassium increases uric acid secretion and lowers plasma uric acid levels, which may be of benefit when losartan potassium is combined with a thiazide diuretic, but which may otherwise lead to uric acid stone formation and possibly to nephropathy. Simple control of blood pressure is no longer an adequate goal in the management of hypertension. Any new antihypertensive agent should also reduce cardiovascular events, prevent or cause regression of end-organ damage such as left ventricular hypertrophy, atherosclerosis and renal failure, and should not impair quality of life. Such data on losartan potassium are not currently available. Losartan potassium is likely to be used in patients who are intolerant of ACE inhibitors, but its future in the management of hypertension will depend on long term tolerability studies and data on its effects beyond simple blood pressure control.

Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174*

Losartan, a selective angiotensin II (AT1) receptor antagonist for hypertension, is metabolized to an active carboxylic acid metabolite, E-3174, which has a longer half-life. To investigate the effects of induction of cytochrome P450 on the metabolism of losartan, we evaluated the effects of phenobarbital on the plasma profiles of losartan and E-3174 in 15 healthy male subjects. Ten subjects received a single 100 mg oral dose of losartan before and during phenobarbital administration (100 mg/day for 16 days), and five subjects received losartan before and during placebo. Urinary excretion of 6-beta-hydroxycortisol (relative to 17-hydroxycorticosteroids) was measured as an endogenous marker of cytochrome P450 induction. The geometric mean area under the plasma concentration-time curve ratios (with/without phenobarbital and 90% confidence intervals) for losartan and its metabolite (E-3174) were 0.795 (0.723, 0.875) and 0.799 (0.778, 0.820), respectively, indicating that phenobarbital treatment significantly but to a clinically minor extent reduced plasma concentrations of losartan and E-3174 (p<0.01). Half-life values of losartan and E-3174 were unchanged. The ratio of 6-beta-hydroxycortisol to 17-hydroxycorticosteroids doubled in the phenobarbital group (p < 0.001) and did not change appreciably in the placebo group.

Angiotensin II antagonists.

Acute blockade of the renin-angiotensin system with the parenterally active angiotensin II antagonist saralasin has been shown to effectively lower blood pressure in a large fraction of patients with essential hypertension and to improve hemodynamics in some patients with congestive heart failure. It is now possible to antagonize chronically angiotensin II at its receptor using the non-peptide angiotensin II inhibitor losartan (DuP 753, MK 954). When administered by mouth, this compound induces a dose-dependent inhibition of the pressor response to exogenous angiotensin II. This effect is closely related to circulating levels of the active metabolite E3174. Preliminary studies performed in hypertensive patients suggest that losartan has a blood pressure lowering action equivalent to that of an ACE inhibitor. Whether this compound will compare favorably with ACE inhibitors requires however further investigation.