Stereoselectivity in the disposition and metabolism of the uricosuric-diuretic agent, indacrinone, in Rhesus monkeys

Journal Article · · Drug Metab. Dispos.; (United States)

OSTI ID:6710552

Zacchei, A G; Dobrinska, M R; Wishousky, T I; Kwan, K C; White, S D

The physiological disposition following intravenous dosing of the separate enantiomers of indacrinone-/sup 14/C (I), and of their major metabolite, 4'-hydroxyindacrinone-/sup 14/C (M), was studied in the rhesus monkey. Pharmacokinetic analysis indicated that the disposition of I and M was stereoselective. In the case of the enantiomers of I, the areas under the curves of plasma concentration vs. time were about sevenfold greater for the (S)(+)- as compared to the (R)(-)-enantiomer. Renal and plasma clearances of (R)(-)-I were five to seven times greater than those of (S)(+)-I. Total urinary recovery of unchanged drug and metabolite accounted for 70% of the administered dose of either enantiomer. The systemic availability of (R)(-)-M from (R)(-)-I was approximately 21% of the dose, whereas that of (S)(+)-M from (S)(+)-I was only 4%. More pronounced differences were noted in the kinetics of metabolite disposition. The AUC values were about 27 times greater for (S)(+)-M than (R)(-)-M, and the renal and plasma clearances were approximately 25-fold higher for (R)(-)-M as compared to (S)(+)-M. The volume of distribution of (S)(+)-M was only 12% of that observed with (R)(+)-M. There was no evidence of glucuronide or sulfate conjugates of any of the enantiomers. These findings are consistent with the pharmacological activity attributed to the different enantiomers.

• Research Organization: Merck Institute for Therapeutic Research, West Point, PA
• OSTI ID: 6710552
• Journal Information: Drug Metab. Dispos.; (United States), Journal Name: Drug Metab. Dispos.; (United States) Vol. 10:1; ISSN DMDSA
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
62 RADIOLOGY AND NUCLEAR MEDICINE
ANIMALS
BIOCHEMISTRY
CARBON 14 COMPOUNDS
CHEMISTRY
DIURETICS
DRUGS
ENANTIOMORPHS
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MACACUS
MAMMALS
METABOLISM
METABOLITES
MONKEYS
PHARMACOLOGY
PRIMATES
STEREOCHEMISTRY
VERTEBRATES