title: Evidence for the O-sulfo derivative of MK-447 as active metabolite of MK-447.
abstract: In contrast with furosemide (and other sulfamoylbenzoic and aryloxyacetic acids loop diuretics), MK-447 was unable to inhibit the [Na+,K+,Cl-] cotransport system in human red blood cells. Indeed, this compound was a very poor ion transport inhibitor (inactive on Ca(2+)-sensitive K+ channels, the Ca2+ pump, the Na+:Mg2+ exchange, the Na+:Li+ countertransport system and the [K+,Cl-] cotransport system, and only inhibiting the [Cl-/HCO3-] exchanger and the Na+,K+ pump at high concentrations). Conversely, its urinary metabolite (O-sulfo)-MK-447 was a very potent inhibitor of the [Na+,K+,Cl-] cotransport system (IC50 of 1.6 +/- 0.5 x 10(-6) M; mean +/- S.D. of four experiments). This compound was a much more potent [Na+,K+,Cl-] cotransport inhibitor than furosemide, and almost as active as bumetanide. In addition, (O-sulfo)-MK-447 was a moderate inhibitor of the [Cl-/HCO3-] exchanger (IC50 of 6 +/- 3 x 10(-5) M, n = 3), its potency being intermediate between that of xipamide and that of furosemide. Interestingly, it exhibited some inhibitory activity against Ca(2+)-sensitive K+ channels but only at high concentrations (it had no effect on the [K+,Cl-] cotransport system, the Ca2+ pump or the Na+:Mg2+ exchanger). The results suggest strongly that the O-sulfo derivative of MK-447 is an active natriuretic metabolite of MK-447. This metabolite may be responsible for the salidiuretic action of MK-447.
authors.affiliation: INSERM, Hôpital Necker, Paris, France.
authors.forename: R P
authors.initials: RP
authors.lastname: Garay
authors.forename: C
authors.initials: C
authors.lastname: Nazaret
authors.forename: E J
authors.initials: EJ
authors.lastname: Cragoe
mesh_terms: D001693:Biological Transport, Active / Q000187:drug effects; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D004232:Diuretics / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D016623:Ion Pumps / Q000187:drug effects; D011188:Potassium / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*
chemical_list: D002712:Chlorides; D004232:Diuretics; D016623:Ion Pumps; D002084:Butylated Hydroxytoluene; C013753:2-aminomethyl-4-t-butyl-6-iodophenol; C072374:O-sulfo-MK 447; D012964:Sodium; D011188:Potassium