Volume 50, Issue 2 p. 160-168

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

Dr Ulrike Werner PhD

Dr Ulrike Werner PhD

Institute of Experimental and Clinical Pharmacology and Toxicology, University of Hamburg, Germany

Search for more papers by this author
Dr Dierk Werner MD

Corresponding Author

Dr Dierk Werner MD

Department of Cardiology, Hospital Stift Bethlehem, Ludwigslust, Germany

Address for correspondence: Ulrike Werner, PhD, Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistr 52, 20146 Hamburg, Germany; e-mail: [email protected].Search for more papers by this author
Dr Svetlana Heinbüchner MD

Dr Svetlana Heinbüchner MD

Department of Cardiology, Helios-Hospital Schwerin, Germany

Search for more papers by this author
Dr Bernhard Graf MD

Dr Bernhard Graf MD

Department of Cardiology, Helios-Hospital Schwerin, Germany

Search for more papers by this author
Dr Hüseyin Ince MD

Dr Hüseyin Ince MD

Department of Cardiology, University of Rostock, Rostock, Germany

Search for more papers by this author
Dr Stefan Kische MD

Dr Stefan Kische MD

Department of Cardiology, University of Rostock, Rostock, Germany

Search for more papers by this author
Dr Petra Thürmann MD

Dr Petra Thürmann MD

Philipp Klee-Institute of Clinical Pharmacology, Helios-Hospital Wuppertal, University of Witten/Herdecke, Germany

Search for more papers by this author
Dr Jörg König PhD

Dr Jörg König PhD

Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany

Search for more papers by this author
Dr Martin F. Fromm MD

Dr Martin F. Fromm MD

Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany

Search for more papers by this author
Dr Oliver Zolk MD

Dr Oliver Zolk MD

Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany

Search for more papers by this author
First published: 07 March 2013
Citations: 49

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 (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.