Biomaterial Database

Evidence for the O-sulfo derivative of MK-447 as active metabolite of MK-447. 1991

R P Garay, and C Nazaret, and E J Cragoe

INSERM, Hôpital Necker, Paris, France.

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.

UI	MeSH Term	Description	Entries
D011188	Potassium	An element in the alkali group of metals with an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the WATER-ELECTROLYTE BALANCE.
D002084	Butylated Hydroxytoluene	A di-tert-butyl PHENOL with antioxidant properties.	Butylhydroxytoluene,2,6-Bis(1,1-dimethylethyl)-4-methylphenol,2,6-Di-t-butyl-4-methylphenol,2,6-Di-tert-butyl-4-methylphenol,2,6-Di-tert-butyl-p-cresol,4-Methyl-2,6-ditertbutylphenol,BHT,Di-tert-butyl-methylphenol,Dibunol,Ionol,Ionol (BHT),2,6 Di t butyl 4 methylphenol,2,6 Di tert butyl 4 methylphenol,2,6 Di tert butyl p cresol,4 Methyl 2,6 ditertbutylphenol,Di tert butyl methylphenol,Hydroxytoluene, Butylated
D002712	Chlorides	Inorganic compounds derived from hydrochloric acid that contain the Cl- ion.	Chloride,Chloride Ion Level,Ion Level, Chloride,Level, Chloride Ion
D004232	Diuretics	Agents that promote the excretion of urine through their effects on kidney function.	Diuretic,Diuretic Effect,Diuretic Effects,Effect, Diuretic,Effects, Diuretic
D004912	Erythrocytes	Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing HEMOGLOBIN whose function is to transport OXYGEN.	Blood Cells, Red,Blood Corpuscles, Red,Red Blood Cells,Red Blood Corpuscles,Blood Cell, Red,Blood Corpuscle, Red,Erythrocyte,Red Blood Cell,Red Blood Corpuscle
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001693	Biological Transport, Active	The movement of materials across cell membranes and epithelial layers against an electrochemical gradient, requiring the expenditure of metabolic energy.	Active Transport,Uphill Transport,Active Biological Transport,Biologic Transport, Active,Transport, Active Biological,Active Biologic Transport,Transport, Active,Transport, Active Biologic,Transport, Uphill
D012964	Sodium	A member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23.	Sodium Ion Level,Sodium-23,Ion Level, Sodium,Level, Sodium Ion,Sodium 23
D016623	Ion Pumps	A general class of integral membrane proteins that transport ions across a membrane against an electrochemical gradient.	Ion Pump,Pump, Ion,Pumps, Ion