title: Gender is an important determinant of the disposition of the loop diuretic torasemide.
abstract: 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 (K(m) = 6.2 microM) 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.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistr 52, 20146 Hamburg, Germany. u.werner@uke.uni-hamburg.de
authors.forename: Ulrike
authors.initials: U
authors.lastname: Werner
authors.forename: Dierk
authors.initials: D
authors.lastname: Werner
authors.forename: Svetlana
authors.initials: S
authors.lastname: Heinbüchner
authors.forename: Bernhard
authors.initials: B
authors.lastname: Graf
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Ince
authors.forename: Stefan
authors.initials: S
authors.lastname: Kische
authors.forename: Petra
authors.initials: P
authors.lastname: Thürmann
authors.forename: Jörg
authors.initials: J
authors.lastname: König
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
authors.forename: Oliver
authors.initials: O
authors.lastname: Zolk
mesh_terms: D002460:Cell Line; D004232:Diuretics / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D016297:Mutagenesis, Site-Directed; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D012737:Sex Factors; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077786:Torsemide
chemical_list: D004232:Diuretics; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D013449:Sulfonamides; D000077786:Torsemide