ORIGINAL ARTICLE Pharmacokinetics, metabolism, bioavailability, tissue distribution and excretion studies of 16α-hydroxycleroda-3, 13(14) Z -dien-15, 16-olide—a novel HMG-CoA reductase inhibitor Tulsankar Sachin Laxman 1,2 & Santosh Kumar Puttrevu 1,2 & Rajesh Pradhan 3 & Anjali Mishra 1 & Sarvesh Verma 1 & Yashpal S. Chhonker 1 & Swarnim Srivastava 1 & Suriya P. Singh 4 & Koneni V. Sashidhara 4 & Rabi Sankar Bhatta 1,3 Received: 15 March 2018 /Accepted: 22 May 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 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 (K p ) 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. Keywords 4655K-09 . HMG-CoA reductase inhibitor . Bioavailability . Metabolism . Tissue disposition . Excretion Introduction Hyperlipidemia is the foremost basis for cardiovascular com- plications in which systemic cholesterol and triglyceride levels were predominately elevated. Currently, statins are the frontline therapeutic agents prescribed for the treatment of hypercholesterolemia which intervene the rate-limiting step of cholesterol synthesis through inhibition of HMG-CoA (3- hydroxy-3-methylglutaryl coenzyme A) reductase enzyme. However, serious adverse effects like liver toxicity, acute renal failure, myopathy and rhabdomyolysis were major drawbacks associated with statins (Maron et al. 2000; Furberg and Pitt 2001). Bioassay-guided fractionation lead to the isolation of 16α-hydroxycleroda-3, 13(14) Z -dien-15, 16-olide (referred as 4655K-09) from the leaves of Polyalthia longifolia var. pendula (Sashidhara et al. 2014). In the quest of a safe and efficacious HMG-CoA reductase inhibitor, CSIR-Central Drug Research Institute (CSIR-CDRI) has evaluated 4655K- 09 for its HMG-CoA inhibition potential. It was found to be more efficacious than lovastatin in treatment of high-fat diet- induced dyslipidemia in hamsters (patent granted US8921417B2) (Sashidhara et al. 2014). It is the first in a Tulsankar Sachin Laxman and Santosh Kumar Puttrevu contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-018-1518-0) contains supplementary material, which is available to authorized users. * Rabi Sankar Bhatta rabi.cdri@gmail.com; rabi_bhatta@cdri.res.in 1 Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India 2 Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, Rafi Marg, New Delhi 110001, India 3 Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Rae Bareli 229010, India 4 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India Naunyn-Schmiedeberg's Archives of Pharmacology https://doi.org/10.1007/s00210-018-1518-0