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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 391, Issue 9, pp 965–973 | Cite as

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
  • Santosh Kumar Puttrevu
  • Rajesh Pradhan
  • Anjali Mishra
  • Sarvesh Verma
  • Yashpal S. Chhonker
  • Swarnim Srivastava
  • Suriya P. Singh
  • Koneni V. Sashidhara
  • Rabi Sankar Bhatta
Original Article

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.

Keywords

4655K-09 HMG-CoA reductase inhibitor Bioavailability Metabolism Tissue disposition Excretion 

Notes

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.

Author contribution

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.

Funding information

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.

Supplementary material

210_2018_1518_MOESM1_ESM.docx (216 kb)
ESM 1 (DOCX 216 kb)
210_2018_1518_MOESM2_ESM.docx (19 kb)
ESM 2 (DOCX 18.9 kb)

References

  1. 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 26:559–565CrossRefPubMedGoogle Scholar
  2. Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP (1997) Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 13:407–484CrossRefPubMedGoogle Scholar
  3. 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 33:210–222CrossRefGoogle Scholar
  4. 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 45:530–537CrossRefPubMedGoogle Scholar
  5. 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 8:723–729CrossRefPubMedGoogle Scholar
  6. Davies B, Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10:1093–1095CrossRefPubMedGoogle Scholar
  7. Fan J, de Lannoy IAM (2014) Pharmacokinetics. Biochem Pharmacol 87:93–120CrossRefPubMedGoogle Scholar
  8. 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, MDGoogle Scholar
  9. Furberg CD, Pitt B (2001) Withdrawal of cerivastatin from the world market. Trials 2:1CrossRefGoogle Scholar
  10. Jacobson TA (2006) Statin safety: lessons from new drug applications for marketed statins. Am J Cardiol 97:S44–S51CrossRefGoogle Scholar
  11. Kiortsis D, Filippatos T, Mikhailidis D, Elisaf M, Liberopoulos E (2007) Statin-associated adverse effects beyond muscle and liver toxicity. Atherosclerosis 195:7–16CrossRefPubMedGoogle Scholar
  12. Maron DJ, Fazio S, Linton MF (2000) Current perspectives on statins. Circulation 101:207–213CrossRefPubMedGoogle Scholar
  13. 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 31:1271–1282PubMedGoogle Scholar
  14. 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 46:5206–5211CrossRefPubMedGoogle Scholar
  15. Sashidhara KV, Puri A, Rosaiah JN (2014) Method of treating dyslipidemia using naturally occurring diterpene. Google PatentsGoogle Scholar
  16. Walker D (1999) Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica 29:297–310CrossRefPubMedGoogle Scholar
  17. Wyska E, Pȩkala E, Szymura-Oleksiak J (2006) Interconversion and tissue distribution of pentoxifylline and lisofylline in mice. Chirality 18:644–651CrossRefPubMedGoogle Scholar
  18. 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 30:541–547CrossRefPubMedGoogle Scholar
  19. 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 269:29688–29696PubMedGoogle Scholar
  20. 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 89:105–113CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • 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
  1. 1.Pharmaceutics and Pharmacokinetics DivisionCSIR-Central Drug Research InstituteLucknowIndia
  2. 2.Academy of Scientific and Innovative Research (AcSIR)New DelhiIndia
  3. 3.Department of PharmaceuticsNational Institute of Pharmaceutical Education and Research (NIPER)Rae BareliIndia
  4. 4.Medicinal and Process Chemistry DivisionCSIR-Central Drug Research InstituteLucknowIndia

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