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Naunyn Schmiedebergs Arch Pharmacol ; 391(9): 965-973, 2018 09.
Article in English | MEDLINE | ID: mdl-29876582

ABSTRACT

The present study was designed to investigate the oral bioavailability, metabolism, tissue disposition and excretion of 16α-hydroxycleroda-3, 13(14) Z -dien-15, 16-olide (4655K-09), a novel HMG-CoA reductase inhibitor in male Sprague Dawley (SD) rats. Tissue distribution, oral bioavailability and excretion studies of 4655K-09 were carried out in male SD rats through oral administration at active dose of 25 mg/kg. In vitro metabolism studies were carried out in different rat tissues S9 fractions to evaluate primary organs responsible for conversion of parent 4655K-09 to its major active metabolite K-9T. The quantification of both parent and metabolite in different biological matrices was performed using LC-MS/MS method. The oral bioavailability of 4655K-09 was found to be 30% in male SD rats. The biodistribution study was illustrated in terms of tissue to plasma area under curve (AUC)0-∞ ratio (Kp) revealed the preferential distribution of 4655K-09 and K-9T to target site, i.e. liver. In vitro tissue S9 fraction stability assay demonstrated the rapid and extensive metabolic conversion of 4655K-09 to K-9T, primarily through liver and kidney. Very low amount of parent and metabolite were excreted unchanged in urine and faeces. The present studies established 4655K-09 bioavailability, tissue disposition, excretion and tissue-specific metabolic conversion to K-9T which could assist in its further development as antihyperlipidemic drug.


Subject(s)
Diterpenes, Clerodane/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Diterpenes, Clerodane/blood , Diterpenes, Clerodane/urine , Feces/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/blood , Hydroxymethylglutaryl-CoA Reductase Inhibitors/urine , Injections, Intravenous , Male , Rats, Sprague-Dawley , Tissue Distribution
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