Gender is an important determinant of the disposition of the loop diuretic torasemide.
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Gender is an important determinant of the disposition of the loop diuretic torasemide. / Werner, Ulrike; Werner, Dierk; Heinbüchner, Svetlana; Graf, Bernhard; Ince, Hüseyin; Kische, Stefan; Thürmann, Petra; König, Jörg; Fromm, Martin F; Zolk, Oliver.
In: J CLIN PHARMACOL, Vol. 50, No. 2, 2, 2010, p. 160-168.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Gender is an important determinant of the disposition of the loop diuretic torasemide.
AU - Werner, Ulrike
AU - Werner, Dierk
AU - Heinbüchner, Svetlana
AU - Graf, Bernhard
AU - Ince, Hüseyin
AU - Kische, Stefan
AU - Thürmann, Petra
AU - König, Jörg
AU - Fromm, Martin F
AU - Zolk, Oliver
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - Humans
KW - Male
KW - Female
KW - Sex Factors
KW - Polymorphism, Genetic
KW - dosage
KW - Cell Line
KW - Mutagenesis, Site-Directed
KW - Diuretics administration
KW - Heart Failure drug therapy
KW - Hypertension drug therapy
KW - Organic Anion Transporters genetics
KW - Sulfonamides administration
KW - Humans
KW - Male
KW - Female
KW - Sex Factors
KW - Polymorphism, Genetic
KW - dosage
KW - Cell Line
KW - Mutagenesis, Site-Directed
KW - Diuretics administration
KW - Heart Failure drug therapy
KW - Hypertension drug therapy
KW - Organic Anion Transporters genetics
KW - Sulfonamides administration
M3 - SCORING: Zeitschriftenaufsatz
VL - 50
SP - 160
EP - 168
JO - J CLIN PHARMACOL
JF - J CLIN PHARMACOL
SN - 0091-2700
IS - 2
M1 - 2
ER -
