EXP3174: The Major Active Metabolite of Losartan

Takahashi, Toshiaki; Nishiyama, Akira; Kimura, Shoji; Aki, Yasuharu; Yoshizumi, Masanori; Morita, Kyoji; Abe, Youichi

doi:10.1111/j.1527-3466.1997.tb00327.x

Cited by 18 publications

(16 citation statements)

References 46 publications

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“…However, the AUC EXP-3174 was also significantly increased (by 41.8%) in the presence of 10 mg/kg ticlopidine. EXP-3174 is eliminated by both renal (accounting for 55% of its clearance) and non-renal routes [19] . One explanation could be that the renal elimination and/or further metabolism of EXP-3174 might be affected by ticlopidine, although further metabolism of EXP-3174 has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats

Yang

Cho

2011

Acta Pharmacol Sin

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npg IntroductionLosartan (DuP 753,, an angiotensin II receptor antagonist, has a low side-effect profile and is approved for the treatment of hypertension, alone or in combination with other agents [1] . After oral administration, losartan is almost completely absorbed and extensively metabolized to a carboxylic acid derivative, EXP-3174, mainly by cytochrome P450 (CYP) 2C9 and 3A4 [2] . EXP-3174 is a major active metabolite in both rats and humans and is a more potent inhibitor of angiotensin II receptor than losartan, with high-affinity receptor specificity [3] . Losartan has also been reported to be a substrate of P-glycoprotein (P-gp) [4] . Considering that losartan is a substrate of both CYP enzymes and P-gp, the modulation of CYP and P-gp activities may cause significant changes in the pharmacokinetic profiles of losartan and its active metabolite, EXP-3174.Ticlopidine, a potent antiplatelet agent induced by adenosine diphosphate, is used for the treatment of a variety of platelet-dependent disease states [5] . Several papers recommend ticlopidine as a valuable alternative when patients cannot tolerate aspirin [6,7] . It has been reported that ticlopidine causes significant inhibition of several drugs metabolized by the hepatic CYP enzyme system [8,9] .Clinically, losartan and ticlopidine can be prescribed concomitantly for the prevention or therapy of cardiovascular diseases. However, the pharmacokinetic interaction between ticlopidine and losartan in vivo has not yet been reported. Therefore, the present study aimed to evaluate the effect of ticlopidine on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats. The effects of ticlopidine on P-gp, CYP2C9, and 3A4 activities were also evaluated. Materials and methods ChemicalsLosartan, EXP-3174, L-158.809 (internal standard), acetonitrile, methanol, and tert-butylmethylether were purchased from Merck Corporation (Darmstadt, Germany). Ticlopidine was purchased from Sigma-Aldrich Corporation (St Louis, MO, USA). All other chemicals were of reagent grade, and all solvents were of HPLC grade. Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in ratsSi-hyung YANG 1 , Young-ah CHO 2 , Jun-shik CHOI 3, * Aim: Losartan and antiplatelet agent ticlopidine can be prescribed concomitantly for prevention or therapy of cardiovascular diseases. Hence, the effects of ticlopidine on the pharmacokinetics of losartan and its active metabolite EXP-3174 were evaluated in rats. Methods: Ticlopidine (4 or 10 mg/kg po) was administered 30 min before administration of losartan (9 mg/kg po or 3 mg/kg iv). The activity of human CYP2C9 and 3A4 were measured using the CYP inhibition assay kit. The activity of P-gp was evaluated using rhodamine-123 retention assay in MCF-7/ADR cells. Results: Ticlopidine (10 mg/kg) significantly increased the areas under the plasma concentration-time curves (AUCs) and peak plasma concentration (C max ) of oral losartan (9 mg/kg), as well as the AUCs of the active metabolite EXP-3174. Ticlopid...

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Section: Discussionmentioning

confidence: 99%

Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats

Yang

Cho

2011

Acta Pharmacol Sin

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“…More than 99% of both losartan and its active metabolite bind to plasma proteins. Losartan has volume of distribution of 34 L. The average plasma clearance of losartan and LCA is approximately 600 and 50 mL/min, respectively . Approximately 14% of losartan is converted to its active metabolite.…”

Section: Evidence Of Formation Of Losartan Carboxylic Acid and Its Phmentioning

confidence: 99%

“…Therefore, it can still be detected in plasma 24 h after a single oral administration of losartan. Circulating plasma radioactivity following administration of C14‐labeled losartan potassium primarily was attributed to losartan and its active metabolite …”

Section: Evidence Of Formation Of Losartan Carboxylic Acid and Its Phmentioning

confidence: 99%

“…Following oral administration, about 4% and 6% of the dose was recovered in urine in unchanged form and as active metabolite, respectively . Both losartan and LCA show linear pharmacokinetics (PK) up to oral doses of 200 mg.…”

Section: Evidence Of Formation Of Losartan Carboxylic Acid and Its Phmentioning

confidence: 99%

“…Both losartan and LCA show linear pharmacokinetics (PK) up to oral doses of 200 mg. Plasma concentrations of losartan and LCA after oral administration decline polyexponentially with a terminal half‐life of about 2 and 6–9 h, respectively …”

Section: Evidence Of Formation Of Losartan Carboxylic Acid and Its Phmentioning

confidence: 99%

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Significance of Metabolites in Bioequivalence: Losartan Potassium as a Case Study

Charoo¹,

Cristofoletti²,

Khatri³

et al. 2014

Journal of Pharmaceutical Sciences

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Pharmacokinetics of a Fixed‐Dose Combination of Amlodipine/Losartan and Chlorthalidone Compared to Concurrent Administration of the Separate Components

Jeon

Moon

Park

et al. 2021

Clinical Pharm in Drug Dev

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Hypertension is more effectively treated with coadministration of 2 or more antihypertensive drugs than with high-dose monotherapy. Therefore, calcium channel blockers, angiotensin II receptor blockers, and thiazides are coadministered to treat hypertension. The objective of this study was to compare the pharmacokinetic (PK) profiles of HCP1401, a fixed-dose combination of amlodipine 5 mg, losartan 100 mg, and chlorthalidone 25 mg, with the separate components (loose combination) of amlodipine/losartan 5/100 mg and chlorthalidone 25 mg. A randomized, open-label, singledose, 2-way crossover study was conducted. Blood samples for amlodipine and chlorthalidone were collected for up to 144 hours after dosing, whereas those for losartan were collected up to 48 hours after dosing. The PK parameters of these drugs were calculated using a noncompartmental method. Sixty subjects completed the study. The geometric mean ratios and 90% confidence intervals of maximum plasma concentration and area under the concentration-time curve to the last measurable point for amlodipine, losartan, and chlorthalidone were within the conventional bioequivalence range of 0.80 to 1.25. There were no clinically significant changes in safety assessments, and the treatments were well tolerated. The PK characteristics and tolerability profiles of a single oral FDC of amlodipine, losartan, and chlorthalidone were equivalent to those of individual tablets in a loose combination.

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EXP3174: The Major Active Metabolite of Losartan

Abstract: Kew Words: Angiotensin 11 type-1 receptor antagonist-EXP3 174-Losartan.

Cited by 18 publications

References 46 publications

Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats

Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats

Significance of Metabolites in Bioequivalence: Losartan Potassium as a Case Study

Pharmacokinetics of a Fixed‐Dose Combination of Amlodipine/Losartan and Chlorthalidone Compared to Concurrent Administration of the Separate Components

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