CRE-10904 [2-(PARA-FLUOROPHENOXY), 1-(ORTHO-HYDROXYPHENYL)-ETHANE] - A NEW DIURETIC AND ANTIHYPERTENSIVE DRUG ACTING BY INVIVO SULFATION

  • 1 November 1990
    • journal article
    • research article
    • Vol. 255  (2) , 415-422
Abstract
CRE 10904 [2-(p-fluorophenoxy), 1-O-hydroxyphenol)-ethane, the leading compound of a new family of loop diuretic and antihypertensive agents; 1-aryl, 2-aryloxy-ethanes]induced high-ceiling natriuretic action in dogs and rats, but was completely inactive in pigs. High-performance liquid chromatography determinations revealed that all CRE 10904 (p.o. or i.v. administered) was rapidly sulfo-conjugated in dogs and rats, and glucuronoconjugated in pigs. The (O-sulfonyl)-CRE10904 metabolite (or simply CRE 11296) rapidly appeared in plasma, reached a concentration peak at about 40 min and disappeared with a half-life time of about 3 hr. The urinary excretion of CRE 11296 was correlated with the natriuretic activity of CRE 10904. Moreover, CRE 11296 was a powerful natriuretic compound in rats and dogs, and even in pigs, i.v. CRE 11296 induced transient natriuresis (just before its rapid hydrolysis and glucurono-conjugation). Studies in human red blood cells revealed that: 1) CRE 11296 was a potent inhibitor of the [Na+,K+,Cl-]-contransport system (IC50 of 1.5 .+-. 0.3 .times. 10-5 M; mean .+-. S.E.M. of 5 experiments), slightly more powerful than furosemide (IC50 of 2 .times. 10-5 M), 2) it was the only diuretic drug potently inhibiting the [K+,Cl-]-cotransport system (IC50 of 2.1 .+-. 0.6 .times. 10-5 M; N = 3) and the [Cl/HCO3-] exchanger (IC50 of 4.5 .+-. 1.0 .times. 10-5 M: N = 3) and 3) CRE 10904 and its glucuronide were much less potent Cl- transport inhibitors. In conclusion, our results strongly support the following mechanism of action: 1) CRE 10904 undergoes rapid and complete in vivo sulfation, 2) the sulfate metabolite is secreted into the proximal tubule (by the weak-acid carrier) and 3) high concentrations of the compound reach the luminal border of Henle''s loop, where the R.sbd.O.sbd.SO3- group inhibits the [Na+,K+,Cl-]-cotransport system at the chloride-receptor site.

This publication has 9 references indexed in Scilit: