Skip to main content
SpringerLink
Log in

Preclinical pharmacokinetics and interspecies scaling of ragaglitazar, a novel biliary excreted PPAR dual activator

  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Summary

Allometric scaling has been used as an effective tool for the prediction of human pharmacokinetic parameters. Allometry has been a useful approach for the analysis of compounds that are eliminated unchanged in the urine and/or exhibit similar metabolic patterns across species. However, it has been a challenging issue to correctly predict human pharmacokinetic parameters for drugs that are eliminated intact and/or as conjugates in the bile. Ragaglitazar is a novel, non-thiazolidinedione peroxisome proliferator-activated receptor (PPAR) α- and γ-agonist. In our investigation, preclinical pharmacokinetic data on ragaglitazar were gathered for several animal species (mice, rats, rabbits and dogs). Ragaglitazar when administered orally has shown a low clearance rate (Cl/F; <5% of hepatic blood flow) in mice, rats and rabbits and a moderately high Cl/F in dogs (>15% of hepatic blood flow). A qualitative estimation of rat bile has unequivocally confirmed the elimination of ragaglitazar in the bile. The human pharmacokinetic data are also indicative of the involvement of enterohepatic biliary recycling. In order to predict key parameters such as Cl/F and volume of distribution (V/F), simple allometry was the approach adopted at the onset. Although V/F scaled adequately, it failed to accurately predict human Cl/F. Therefore, standard correction factors such as maximum life span potential (MLP) and brain weight were also included. Although such modifications improved the linearity (r 2>0.9), they failed to predict the investigated values. Further incorporation of correction factors particularly relevant to biliary excreted drugs improved the prediction of these values. Interestingly, the exclusion of dog data from the interspecies scaling considerably improved the prediction of both Cl/F and V/F.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Di Masi J.A. (1994): Risks, regulation, and rewards in new drug development in the United States. Regul. Toxicol. Pharmacol., 19, 228–235.

    Article  Google Scholar 

  2. Kuhlmann J. (1997): Drug research: from the idea to the product. Int. J. Clin. Pharmacol. Ther., 35, 541–552.

    CAS  PubMed  Google Scholar 

  3. Ings R.M.J. (1990): Interspecies scaling and comparisons in drug development and toxicokinetics. Xenobiotica, 20, 1201–1231.

    Article  CAS  PubMed  Google Scholar 

  4. Ritschel W.A., Vachharajani N.N., Johnson R.D., Hussain A.S. (1992): The allometric approach for interspecies scaling of pharmacokinetic parameters. Comp. Biochem. Physiol. C, 103, 249–253.

    Article  CAS  PubMed  Google Scholar 

  5. Lin J.H. (1998): Applications and limitations of interspecies scaling andin vitro extrapolation in pharmacokinetics. Drug Metab. Dispos., 12, 1202–1212.

    Google Scholar 

  6. Bachmann K., Pardoe D., White D. (1996): Scaling basic toxicokinetic parameters from rat to man. Environ. Health Perspect., 104, 400–407.

    Article  CAS  PubMed  Google Scholar 

  7. Mahmood I., Balian J.D. (1996): Interspecies scaling: predicting clearance of drugs in humans. Three different approaches. Xenobiotica, 26, 887–895.

    CAS  Google Scholar 

  8. Obach R.S., Baxter J.G., Liston T.E., Silber B.M., Jones B.C., Maclntyre F., Ranee D.J., Wastall P. (1997): The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J. Pharmacol. Exp. Ther., 283, 46–58.

    CAS  PubMed  Google Scholar 

  9. Riviere J.E., Martin-Jimenez T., Sundlof S.F., Craigmill A.L. (1997): Interspecies allometric analysis of the comparative pharmacokinetics of 44 drugs across veterinary and laboratory animal species. J. Vet. Pharmacol. Ther., 20, 453–463.

    Article  CAS  PubMed  Google Scholar 

  10. Vamceq J., Latruffe N. (1999): Medical significance of peroxisome proliferator-activated receptors. Lancet, 354, 141–148.

    Article  Google Scholar 

  11. Bailey C.J. (2000): Potential new treatments for type 2 diabetes. Trends Pharmacol. Sci., 21, 259–265.

    Article  CAS  PubMed  Google Scholar 

  12. Ranjan C, Reeba K.V., Suresh J., Parimal M., Jagadeeshan H., Rajagopalan R. (2001): (−)DRF 2725, a novel dual activator of PPARα and PPARγ with unique antidiabetic and hypolipidemic activity. Diabetes, 50 (Suppl. 2), 432-P. A108.

    Google Scholar 

  13. Lohray B.B., Vidya B.L., Ashok C.B., Shivaramayya K., Rajamohan R.P., Srinivas P., Ranjan C., Reeba K.V., Parimal M., Suresh J., Mamidi N.V.S.R., Rajagopalan R. (2001): (−)3-[4-[2-(Phenoxazin-10-y])ethoxy]phenyl]-2-ethoxy-propanoi cacid [(−)DRF 2725]: a dual PPAR agonist with potent antihyper-glycemic and lipid modulating activity. J. Med. Chem., 44, 2675–2678.

    Article  CAS  PubMed  Google Scholar 

  14. Mamanoor P.K., Srinivas R.D., Ravi K.B.D., Ranjan C., Kanthi K., Rajagopalan R. (2002): Antihypertensive potential of the dual PPARα and γ agonist ragaglitazar. Diabetes, 51(Suppl. 2), 144-OR, A36.

    Google Scholar 

  15. Reeba K.V., Jagadeeshan H., Cynthia G., Ramanujam R., Ranjan C. (2002) Diabetes, 51 (Suppl. 2), 584-P, A144.

    Google Scholar 

  16. Jagannath K., Rao C.M., Mullangi R., Rao N.V.S.M., Srinivas N.R. (2004): Intravenous pharmacokinetics, oral bioavailability and dose proportionality of ragaglitazar, a novel PPAR-dual activator in rate. Biopharm. Drug Dispos., 25, 323–328.

    Article  CAS  PubMed  Google Scholar 

  17. Skrumsager B.K., Nielsen K.K., Muller M., Pabst G., Drake P.G., Edsberg B. (2003): Ragaglitazar: the pharmacokinetics. pharmacodynamics, and tolerability of a novel dual PPAR-α and γ agonist in healthy subjects and patients with Type 2 diabetes. J. Clin. Pharmacol., 43, 1244–1256.

    Article  CAS  PubMed  Google Scholar 

  18. Jagannath K., Ramesh M., Rao N.V.S.M., Rajagopalan R. (2002): Quantitative determination of ragaglitazar in rat plasma by HPLC: validation and application in pharmacokinetic study. Biomed. Chromatogr., 16, 495–499.

    Article  Google Scholar 

  19. Yamaoka K., Nakagawa T., Uno T. (1978): Application of Akaike’s Information criterion (AIC) to the evaluation of linear pharmacokinetics equations. J. Pharmacokinet. Biopharm., 6, 165–175.

    Article  CAS  PubMed  Google Scholar 

  20. Gabrielson J., Weiner D. (1997): Pharmacokinetic and pharmacodynamic data analysis: concepts and applications. Apotekarsocieteten, Stockholm.

    Google Scholar 

  21. Boxenbaum H. (1982): Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics. J. Pharmacokinet. Biopharm., 10, 201–227.

    Article  CAS  PubMed  Google Scholar 

  22. Mahmood I., Balian J.D. (1996): Interspecies scaling: predicting pharmacokinetic parameters of antiepileptic drugs in humans from animals with special emphasis on clearance. J. Pharm. Sci., 85, 411–414.

    Article  CAS  PubMed  Google Scholar 

  23. Mahmood I., Sahajwalla C. (2002): Interspecies scaling of biliary excreted drugs. J. Pharm. Sci., 91, 1908–1914.

    Article  CAS  PubMed  Google Scholar 

  24. Mahmood I. (2005): Interspecies scaling of biliary excreted drugs: a comparison of several methods. J. Pharm. Sci., 94, 883–892.

    Article  CAS  PubMed  Google Scholar 

  25. Izumi T., Enomoto S., Hosiyama K., Sasahara K., Shibukawa A., Nakagawa T., Sugiyama Y. (1996): Prediction of the human pharmacokinetics of troglitazone, a new and extensively me-tabolized antidiabetic agent, after oral administration, with an animal scale-up approach. J. Pharmacol. Exp. Ther., 277, 1630–1641.

    CAS  PubMed  Google Scholar 

  26. Davies B., Morris T. (1993): Physiological parameters in laboratory animals and humans. Pharm. Res., 10, 1093–1095.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics, Discovery Research, Dr Reddy’s Laboratories Ltd, Miyapur, Hyderabad 49, India

    Venkata V. Pavankuamr, C. A. Vinu & Ramesh Mullangi

  2. Drug Development, Discovery Research, Dr Reddy’s Laboratories Ltd, Miyapur, Hyderabad 49, India

    Nuggehally R. Srinivas

Authors
  1. Venkata V. Pavankuamr
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. A. Vinu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ramesh Mullangi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nuggehally R. Srinivas
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pavankuamr, V.V., Vinu, C.A., Mullangi, R. et al. Preclinical pharmacokinetics and interspecies scaling of ragaglitazar, a novel biliary excreted PPAR dual activator. Eur. J. Drug Metabol. Pharmacokinet. 32, 29–37 (2007). https://doi.org/10.1007/BF03190987

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03190987

Keywords

Search

Navigation