polymorphisms and the interindividual variability in pharmacokinetics and pharmacodynamics of the loop diuretic drug torsemide

Vormfelde, Stefan Viktor; Engelhardt, Sabine; Zirk, Alexandra; Meineke, Ingolf; Tuchen, Franziska; Kirchheiner, Julia; Brockmöller, Jürgen

doi:10.1016/j.clpt.2004.08.024

Cited by 44 publications

(50 citation statements)

References 25 publications

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“…[9][10][11][12][13] Moreover, polymorphisms in the gene encoding the organic anion transporting polypeptide OATP1B1 (SLCO1B1), which mediates the hepatocellular uptake of drugs, have been reported to influence torasemide disposition. 9,14 Because torasemide is extensively bound to plasma protein (>99%), very little of the drug enters urine via glomerular filtration.…”

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confidence: 99%

Gender Is an Important Determinant of the Disposition of the Loop Diuretic Torasemide

Werner

Heinbüchner

et al. 2010

The Journal of Clinical Pharma

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Signals from pharmacovigilance studies indicate that women are at higher risk for adverse drug reactions (ADRs) due to diuretics. Despite the long‐term use of torasemide, there are few studies investigating gender differences of torasemide pharmacokinetics in the hospital setting. Therefore, torasemide pharmacokinetics were investigated in 90 patients (45 women, 45 men) during steady‐state conditions. Torasemide elimination was significantly reduced in women compared with men (eg, body‐weight‐normalized area under the concentration‐time curve: 42.1 ± 20.4 vs 30.9 ± 10.3 kg•h/L; P < .001). Among the investigated genetic factors [SLC22A11(OAT4), SLCO1B1(OATP1B1), CYP2C9], only the SLCO1B1c.521T>C polymorphism had a significant influence on torasemide pharmacokinetics. Using cell lines expressing OATP1B1, the authors identified torasemide as OATP1B1 substrate (Km = 6.2 μM) with a significant reduction of uptake by the 521C‐variant. Taken together, gender differences in torasemide pharmacokinetics are likely to contribute to a higher rate of ADRs in women, which has, for example, been observed in a German Pharmacovigilance Project with 66% of hospitalizations due to torasemide ADRs occurring in women.

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confidence: 99%

Gender Is an Important Determinant of the Disposition of the Loop Diuretic Torasemide

Werner

Heinbüchner

et al. 2010

The Journal of Clinical Pharma

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“…21 As over 80% of interindividual variation in the metabolic clearance of torsemide remained unexplained, we investigate a larger population with an extended set of analysed polymorphisms. The CYP2C9*2 and the CYP2C9*3 allele each defined exactly one CYP2C9 haplotype.…”

Section: Discussionmentioning

confidence: 99%

“…21,49 The limit of quantification was 10 ng/ml for all analytes from plasma samples and 1 ng/ml for all analytes from urine samples. Pharmacokinetic analysis was performed with the nonparametric analysis module of the WinNonlin software, version 2.1.…”

Section: Drug Concentration and Pharmacokinetic Analysismentioning

confidence: 99%

“…A subpopulation of the study population presented here formed the population published earlier. 21 After an overnight fast, 10 mg torsemide (Unat; Roche Diagnostics GmbH, Mannheim, Germany) was administered orally after the subjects had emptied their bladder. Volunteers fasted until 4 h after drug administration.…”

Section: Clinical Studymentioning

confidence: 99%

“…Torsemide clearance was greatly reduced in carriers of the CYP2C9*3 variant but not in carriers of the CYP2C9*2 variant in accordance with in vitro findings. 2,19,21,22 Torsemide may therefore be a valuable CYP2C9 probe drug with specific properties compared to the other commonly used substrates tolbutamide, 23 warfarin [24][25][26] or losartan. 27 Phenotyping unselected samples has lead to the identification of functionally relevant genetic polymorphisms.…”

Section: Introductionmentioning

confidence: 99%

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Genetic variation at the CYP2C locus and its association with torsemide biotransformation

et al. 2006

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In 97 unselected volunteers and two additional homozygous carriers of CYP2C9*3, we investigated the oral clearance of torsemide in relation to 37 polymorphisms at the CYP2C gene locus. Torsemide total oral clearance was linearly associated with the number of CYP2C9*3 alleles (geometric mean: 59, 40 and 20 ml/min in carriers of no, one and two alleles) and so were the methyl-and ring-hydroxylation but not the carboxylation clearance. Haplotypes including the CYP2C9*3 allele were similarly associated with the clearances but no other variant and no haplotype not including the CYP2C9*3 variant. The extended haplotype length (EHL) of the CYP2C9 haplotypes was positively associated with higher activity of the gene product. Torsemide total oral clearance was predictable with r 2 ¼ 82.1% using plasma concentrations at 0.5, 1, 2 and 24 h. In conclusion, torsemide's biotransformation strongly depended on the CYP2C9*3 variant but no other. Higher clearance CYP2C9 haplotypes appear to be evolutionarily selected.

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Torsemide vs Furosemide After Discharge and All-Cause Mortality in Patients With Heart Failure

Wolowich

2023

JAMA

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polymorphisms and the interindividual variability in pharmacokinetics and pharmacodynamics of the loop diuretic drug torsemide

Cited by 44 publications

References 25 publications

Gender Is an Important Determinant of the Disposition of the Loop Diuretic Torasemide

Gender Is an Important Determinant of the Disposition of the Loop Diuretic Torasemide

Genetic variation at the CYP2C locus and its association with torsemide biotransformation

Torsemide vs Furosemide After Discharge and All-Cause Mortality in Patients With Heart Failure

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