Enhancement of uricosuric properties of indacrinone by manipulation of the enantiomer ratio

Abstract

Racemic indacrinone [[(6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-2-phenyl-1H-inden-5-yl)oxy] acetic acid] is a high-ceiling, relatively long-acting diuretic. Both enantiomers have uricosuric activity, but the diuretic activity resides predominantly in the (-) enantiomer. Usual therapeutic doses of racemic indacrinone have only transient uricosuric activity, i.e., as with other diuretics, hyperuricemia occurs. Healthy men (65) participated in a multicenter, double-blind, randomized, balanced, incomplete-block study comparing the effects on plasma urate and urate clearance of indacrinone (-) enantiomer 10 mg given concomitantly with 0, 10, 20, 40 and 80 mg (+) enantiomer (10/0, 10/10, 10/20, 10/40, 10/80), as single daily doses for 7 days. Hydrochlorothiazide (HCTZ) 50 mg daily and ticrynafen (T) 250 mg daily were controls. Each subject received 2 of the 7 treatments, so that there were 18 subjects/treatment. On days 7-8, morning (mean of 0 h values on days 7 and 8), HCTZ, 10/0, 10/10 and 10/20 elevated plasma urate by 8-16%, 10/40 was approximately isouricemic, and 10/80 and T lowered plasma urate by 13% and 41%. There were corresponding changes in urate clearance.