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.
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References
Bhatta R, Kumar D, Chhonker Y, Kumar D, Singh SP, Sashidhara KV, Jain G (2012) Simultaneous estimation of 16α-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide from Polyalthia longifolia and its metabolite in hamster plasma: application to pharmacokinetic study. Biomed Chromatogr 26:559–565
Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP (1997) Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 13:407–484
Casey Laizure S, Herring V, Hu Z, Witbrodt K, Parker RB (2013) The role of human carboxylesterases in drug metabolism: have we overlooked their importance? Pharmacother: J Human Pharmacol Drug Ther 33:210–222
Chandasana H, Chhonker YS, Prasad YD, Laxman TS, Anil Kumar K, Dikshit DK, Bhatta RS (2015) Pharmacokinetics and tissue distribution study of novel potent antiplatelet agent S007-867 in mice using HPLC-MS/MS. Xenobiotica 45:530–537
Chandasana H, Chhonker YS, Laxman TS, Prasad YD, KS AK, Dikshit DK, Bhatta RS (2016) Assessement of the pharmacokinetics, tissue distribution and excretion studies of a novel antiplatelet agent S007-867, following administration to rats. Drug Test Anal 8:723–729
Davies B, Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10:1093–1095
Fan J, de Lannoy IAM (2014) Pharmacokinetics. Biochem Pharmacol 87:93–120
Food U, Administration D (2013) FDA guidance for industry: bioanalytical method validation. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research: Rockville, MD
Furberg CD, Pitt B (2001) Withdrawal of cerivastatin from the world market. Trials 2:1
Jacobson TA (2006) Statin safety: lessons from new drug applications for marketed statins. Am J Cardiol 97:S44–S51
Kiortsis D, Filippatos T, Mikhailidis D, Elisaf M, Liberopoulos E (2007) Statin-associated adverse effects beyond muscle and liver toxicity. Atherosclerosis 195:7–16
Maron DJ, Fazio S, Linton MF (2000) Current perspectives on statins. Circulation 101:207–213
Parker RA, Clark RW, Sit S-Y, Lanier TL, Grosso RA, Wright J (1990) Selective inhibition of cholesterol synthesis in liver versus extrahepatic tissues by HMG-CoA reductase inhibitors. J Lipid Res 31:1271–1282
Sashidhara KV, Singh SP, Srivastava A, Puri A, Chhonker YS, Bhatta RS, Shah P, Siddiqi MI (2011) Discovery of a new class of HMG-CoA reductase inhibitor from Polyalthia longifolia as potential lipid lowering agent. Eur J Med Chem 46:5206–5211
Sashidhara KV, Puri A, Rosaiah JN (2014) Method of treating dyslipidemia using naturally occurring diterpene. Google Patents
Walker D (1999) Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica 29:297–310
Wyska E, Pȩkala E, Szymura-Oleksiak J (2006) Interconversion and tissue distribution of pentoxifylline and lisofylline in mice. Chirality 18:644–651
Xie M, Yang D, Liu L, Xue B, Yan B (2002) Human and rodent carboxylesterases: immunorelatedness, overlapping substrate specificity, differential sensitivity to serine enzyme inhibitors, and tumor-related expression. Drug Metab Dispos 30:541–547
Yan B, Yang D, Brady M, Parkinson A (1994) Rat kidney carboxylesterase. Cloning, sequencing, cellular localization, and relationship to rat liver hydrolase. J Biol Chem 269:29688–29696
Yeung CK, Fujioka Y, Hachad H, Levy RH, Isoherranen N (2011) Are circulating metabolites important in drug–drug interactions?: quantitative analysis of risk prediction and inhibitory potency. Clin Pharmacol Ther 89:105–113
Acknowledgements
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.
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We are thankful to BSC0102 (THUNDER) project for funding and the Director, CSIR-CDRI, for providing facilities and infrastructure for the study.
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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.
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Laxman, T.S., Puttrevu, S.K., Pradhan, R. et al. 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. Naunyn-Schmiedeberg's Arch Pharmacol 391, 965–973 (2018). https://doi.org/10.1007/s00210-018-1518-0
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DOI: https://doi.org/10.1007/s00210-018-1518-0