Metabolism of kadsurenone and 9,10-dihydrokadsurenone in rhesus monkeys and rat liver microsomes

Journal Article · Thu Sep 01 00:00:00 EDT 1988 · Drug Metab. Dispos.; (United States)

OSTI ID:6071405

Thompson, K L; Chang, M N; Chabala, J C; Chiu, S H; Eline, D; Hucker, H B; Sweeney, B M; White, S D; Arison, B H; Smith, J L

The metabolism of the PAF antagonists kadsurenone and tritium-labeled 9,10-dihydrokadsurenone was studied in rhesus monkeys and rat liver microsomes. The monkey metabolites of the two drugs were isolated as their glucuronide conjugates from the urine of iv dosed males. The metabolites from both monkey and microsomal metabolism were purified by reverse phase HPLC and identified by spectral (NMR, UV, and mass spectrometric) analysis. The principal pathway of biotransformation of the tritium-labeled 9,10-dihydrokadsurenone in monkeys was hydroxylation of the C-5 propyl side chain to give two metabolites, 10-hydroxy-9,10-dihydrokadsurenone and 9-hydroxy-9,10-dihydrokadsurenone. These compounds were excreted as glucuronides. Microsomal incubation of tritium-labeled 9,10-dihydrokadsurenone yielded the 10-, 9-, and 8-hydroxy-9,10-dihydrokadsurenone as major metabolites. Kadsurenone was also metabolized at the C-5 side chain, an allyl group. The monoglucuronide of 9,10-dihydroxykadsurenone was isolated from monkey urine. Spectral analysis was not definitive as to the site of conjugation, and the structure of the metabolite was assigned as the C-10 conjugate. A major metabolite of rat liver microsomal incubation of kadsurenone was 9,10-dihydroxykadsurenone.

• Research Organization: Merck Sharp and Dohme Research Laboratories, Rahway, NJ (USA)
• OSTI ID: 6071405
• Journal Information: Drug Metab. Dispos.; (United States), Journal Name: Drug Metab. Dispos.; (United States) Vol. 16:5; ISSN DMDSA
• Country of Publication: United States
• Language: English

Related Subjects

550501 -- Metabolism-- Tracer Techniques
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
BENZOFURANS
BIOLOGICAL PATHWAYS
BODY
CHROMATOGRAPHY
DIGESTIVE SYSTEM
FURANS
GLANDS
HETEROCYCLIC COMPOUNDS
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
LIQUID COLUMN CHROMATOGRAPHY
LIVER
MAMMALS
MASS SPECTRA
METABOLISM
MONKEYS
NMR SPECTRA
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
PRIMATES
RATS
RODENTS
SEPARATION PROCESSES
SPECTRA
TRACER TECHNIQUES
TRITIUM COMPOUNDS
ULTRAVIOLET SPECTRA
VERTEBRATES