CRE 10904 [2-(p-fluorophenoxy), 1-(o-hydroxyphenyl)-ethane]: a new diuretic and antihypertensive drug acting by in vivo sulfation.
CRE 10904 [2-(p-fluorophenoxy), 1-(o-hydroxyphenyl)-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 glucurono-conjugated 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-]-cotransport system (IC50 of 1.5 +/- 0.3 x 10(-5) M; mean +/- S.E.M. of 5 experiments), slightly more powerful than furosemide (IC50 of 2 x 10(-5) M), 2) it was the only diuretic drug potently inhibiting the [K+,Cl-]-cotransport system (IC50 of 2.1 +/- 0.6 x 10(-5) M; N = 3) and the [Cl/HCO3-] exchanger (IC50 of 4.5 +/- 1.0 x 10(-5) M; N = 3) and 3) CRE 10904 and its glucuronide were much less potent Cl- transport inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
Garay
R P
RP
INSERM U7, Hôpital Necker, Paris, France.
Labaune
J P
JP
Mesangeau
D
D
Nazaret
C
C
Imbert
T
T
Moinet
G
G
D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism / Q000494:pharmacology*; D001639:Bicarbonates / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D004232:Diuretics / Q000378:metabolism / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D008297:Male; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism
D000959:Antihypertensive Agents; D001639:Bicarbonates; D002712:Chlorides; D004232:Diuretics; D010636:Phenols; D013431:Sulfates; C066461:CRE 10904; D012964:Sodium; D011188:Potassium