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.
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The authors T.S.L and S.P are thankful to the council of scientific & industrial research (CSIR) for providing the research fellowship. The CSIR-CDRI manuscript number of this article is 71/2018/RSB.
The author RSB designed experimental plan and provided necessary facilities. TSL and SKP are performed LC-MS/MS based sample analysis and wrote the manuscript. KVS and SPS synthesized the compound. The author RP, SV, AM and SS are conducted all in vitro-in vivo experiments. YSC analyzed the experimental data. All authors read and approved the manuscript.
We are thankful to BSC0102 (THUNDER) project for funding and the Director, CSIR-CDRI, for providing facilities and infrastructure for the study.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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