99300-68-2Relevant articles and documents
Human hepatic cytochrome P450 2C9 catalyzes the rate-limiting pathway of torsemide metabolism
Miners,Rees,Valente,Veronese,Birkett
, p. 1076 - 1081 (2007/10/03)
Tolyl methylhydroxylation is the rate-limiting step in the elimination of torsemide, a newly developed diuretic, in humans in vivo. Kinetic and inhibitor studies with human liver microsomes and complementary DNA-expressed enzyme were performed to identify the cytochrome P450 (CYP) isoform responsible for torsemide tolyl methylhydroxylation to predict factors that might alter clearance in patients receiving torsemide. As in vivo, tolyl methylhydroxylation was the major biotransformation pathway in human liver microsomes. Microsomal tolyl methylhydroxylation kinetics followed Michaelis- Menten kinetics, with the mean apparent K(m) for the reaction being 11.2 ± 1.3 μM. The microsomal reaction was almost completely abolished by the specific CYP2C9 inhibitor sulfaphenazole and was inhibited competitively by the alternative CYP2C9 substrate tolbutamide. Torsemide tolyl methylhydroxylase activity in microsomes from 16 human livers correlated significantly (r(s) = .81-.88) with tolbutamide and phenytoin hydroxylation, both CYP2C9-mediated reactions. Complementary DNA-expressed CYP2C9 catalyzed torsemide tolyl methylhydroxylation with an apparent K(m) (23 μM) similar to that observed for human liver microsomes and the IC50 values for sulfaphenazole inhibition of the reaction were essentially identical for the two enzyme sources. Taken together, these data demonstrate that human hepatic torsemide tolyl methylhydroxylation is catalyzed predominantly, if not solely, by CYP2C9. The implications of this finding for the regulation of torsemide metabolism in vivo are discussed.
Comparison of diuretic effects and pharmacokinetics of torasemide and furosemide after a single oral dose in patients with hydropically decompensated cirrhosis of the liver.
Brunner,von Bergmann,Haecker,von Moellendorff
, p. 176 - 179 (2007/10/02)
In a controlled double-blind randomized clinical trial, the pharmacodynamics and pharmacokinetics of 20 mg torasemide (1-isopropyl-3-([4-(3-methyl-phenylamino)pyridine]-3-sulfonyl)urea) (n = 10) and 40 mg furosemide (n = 9) were compared over 24 h after single oral administration to patients with ascites due to cirrhosis of the liver. The overall 24-h excretion of volume and sodium was not significantly different between patients receiving torasemide or furosemide. The diuretic effect of torasemide, however, was longer in duration than that of furosemide. This was in accordance with the pharmacokinetic behaviour of torasemide and furosemide. The serum elimination half-life of torasemide was longer (4.8 h) than that of furosemide (2.2 h) in these patients and also longer than that in healthy volunteers (3 h). The areas under the serum concentration-time curves for torasemide were higher than in healthy subjects by a factor of 2.5. In parallel with the considerably delayed formation of the diuretically inactive metabolite M5, which is formed via the diuretically active metabolite M1, the serum concentration of M1 was increased in these patients. However, the overall excretion of torasemide and the different metabolites was similar compared to healthy volunteers. These results indicate that the pharmacokinetics and metabolism of torasemide depend on liver function. No adverse reaction were experienced in either group.
