DOI QR코드

DOI QR Code

Evaluation of Pharmacokinetics of Simvastatin and Its Pharmacologically Active Metabolite from Controlled-Release Tablets of Simvastatin in Rodent and Canine Animal Models

  • Received : 2010.10.01
  • Accepted : 2010.11.02
  • Published : 2011.04.30

Abstract

Biotransformation of pharmacologically inactive lactone prodrug simvastatin (SV) into pharmacologically active simvastatin ${\beta}$-hydroxy acid (SVA) exhibits inter-species differences due to variations in amount and activity of esterase enzymes. In this study, we investigated the pharmacokinetics (PK) of SV and its metabolite SVA following oral doses of SV from controlled-release (CR) tablets and immediate-release (IR) tablets in rodent and canine animal models that features different esterase activity. In rat PK study, no SV was detected in plasma for both formulations due to rapid hydrolysis of SV into SVA by plasma esterase. Besides, no significant differences in PK parameters of SV or SVA were observed between both species. In dog PK study, the relative oral bioavailability of CR tablets in terms of SV was 72.3% compared to IR tablets. Regarding formulation differences in dogs, CR tablets exhibited significantly lower $C_{max}$ (p<0.05), and higher $T_{max}$ (p<0.01) and MRT (p<0.01) for both SV and SVA compared to IR tablets. Accordingly, CR tablets of SV with prolonged drug release profiles in both species might be a potential candidate for a more effective delivery of SV with reduced side effects. Besides, similar PK parameters of SV and SVA in both species despite variation in enzyme activities suggested involvement of equally potent biotransformation pathways in these animal species.

Keywords

References

  1. Alberts, A. W. (1988) Discovery, biochemistry and biology of lovastatin. Am. J. Cardiol. 62, 10J-15J. https://doi.org/10.1016/0002-9149(88)90002-1
  2. Alberts, A. W. (1990) Effects of HMG CoA reductase inhibitors on cholesterol synthesis. Drug Invest. 2, 9-17.
  3. Alberts, A. W., Chen, J., Kuron, G., Hunt, V., Huff, J., Hoffman, C., Rothrock, J., Lopez, M., Joshua, H., Harris, E., Patchett, A., Monaghan, R., Currie, S., Stapley, E., Albers-Schonberg, G., Hensens, O., Hirshfi eld, J., Hoogsteen, K., Liesch, J. and Springer, J. (1980) Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterollowering agent. Proc. Natl. Acad. Sci. U.S.A. 77, 3957-3961. https://doi.org/10.1073/pnas.77.7.3957
  4. Black, A. E., Hayes, R. N., Roth, B. D., Woo, P. and Woolf, T. F. (1999). Metabolism and excretion of atorvastatin in rats and dogs. Drug Metab. Dispos. 27, 916-923.
  5. Bradford, R. H., Shear, C. L., Chremos, A. N., Dujovne, C., Downton, M., Franklin, F. A., Gould, A. L., Hesney, M., Higgins, J., Hurley, D. P., Langendorfer, A., Nash, D. T., Pool, J. L. and Schnaper, H. (1991) Expanded clinical evaluation of lovastatin (EXCEL) study results: I. Effi cacy in modifying plasma lipoproteins and adverse event profi le in 8245 patients with moderate hypercholesterolemia. Arch. Intern. Med. 151, 43-49. https://doi.org/10.1001/archinte.151.1.43
  6. Carroll, J. D., Reidy, M., Savundra, P. A., Cleave, N. and McAinsh, J. (1990) Longacting propranolol in the prophylaxis of migraine: a comparative study of two doses. Cephalalgia 10, 101-105. https://doi.org/10.1046/j.1468-2982.1990.1002101.x
  7. Cheng, H., Sutton, S. C., Pipkin, J. D., Zentner, G. M., Rogers, J. D., Schwartz, J. I., Mitchel, Y. B., Grasing, K., Schwartz, M. S., Amin, R. D., Liu, L., Ebel, D. L., Coulter, A., Engle, K., McClelland, G. A., Lui, C. Y. and Rork, G. S. (1993) Evaluation of sustained/controlled-release dosage forms of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors in dogs and humans. Pharm. Res. 10, 1683-1687. https://doi.org/10.1023/A:1018997308946
  8. Curran, M. P. and Goa, K. L. (2003) Lovastatin extended release: A review of its use in the management of hypercholesterolaemia. Drugs 63, 685-699. https://doi.org/10.2165/00003495-200363070-00007
  9. Davidson, M. H., Lukacsko, P., Sun, J. X., Phillips, G., Walters, E., Sterman, A., Niecestro, R. and Friedhoff, L. (2002) A multiple-dose pharmacodynamic, safety, and pharmacokinetic comparison of extended- and immediate-release formulations of lovastatin. Clin. Ther. 24, 112-125. https://doi.org/10.1016/S0149-2918(02)85009-3
  10. Duggan, D. E., Chen, I. W., Bayne, W. F., Halpin, R. A., Duncan, C. A., Schwartz, M. S., Stubbs, R. J. and Vickers, S. (1989) The physiological disposition of lovastatin. Drug Metab. Dispos. 17, 166-173.
  11. Duggan, D. E. and Vickers, S. (1990) Physiological disposition of HMGCoA-reductase inhibitors. Drug Metab. Rev. 22, 333-362. https://doi.org/10.3109/03602539009041088
  12. Goldbeter, A. and Claude, D. (2002) Time-patterned drug administration: insights from a modeling approach. Chronobiol. Int. 19, 157-175. https://doi.org/10.1081/CBI-120002596
  13. Gotto, A. M. Jr. (1997) Results of recent large cholesterol-lowering trials and indications for clinical management. Am. J. Cardiol. 79, 1663-1666. https://doi.org/10.1016/S0002-9149(97)00218-X
  14. Grundy, S. M. (1998) HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N. Engl. J. Med. 319, 24-33.
  15. Halsas, M., Hietala, J., Veski, P., Jurjenson, H. and Marvola, M. (1999) Morning versus evening dosing of ibuprofen using conventional and timecontrolled release formulations. Int. J. Pharm. 189, 179-185. https://doi.org/10.1016/S0378-5173(99)00250-1
  16. Hebert, P. R., Gaziano, J. M., Chanm K. S. and Hennekens, C. H. (1997) Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA 278, 313-321. https://doi.org/10.1001/jama.278.4.313
  17. Higaki, K., Yamashita, S. and Amidon, G. L. (2001) Time-dependent oral absorption models. J. Pharmacokinet. Pharmacodyn. 28, 109-128.
  18. Kostner, G. M., Gavish, D., Leopold, B., Bolzano, K., Weintraub, M. S. and Breslow, J. L. (1989) HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a)levels. Circulation. 80, 1313-1319. https://doi.org/10.1161/01.CIR.80.5.1313
  19. Lamson, M., Phillips, G., Shen, J., Lukacsko, P., Friedhoff, L. and Niecestro, R. M. (2002) Pharmacokinetics of lovastatin extendedrelease dosage form (Lovastatin XL) in healthy volunteers. Biopharm. Drug Dispos. 23, 143-149. https://doi.org/10.1002/bdd.304
  20. Le Couteur, D. G., Martin, P. T., Bracs, P., Black, A., Hayes, R., Woolf, T. and Stern, R. (1996) Metabolism and excretion of [14C]-atorvastatin in patients with T-tube drainage. Proc. Aust. Soc. Clin. Exp. Pharmacol. Toxicol. 3, 153-158.
  21. Lobenberg, R., Kim, J. S. and Amidon, G. L. (2005) Pharmacokinetics of an immediate release, a controlled release and a two pulse dosage form in dogs. Eur. J. Pharm. Biopharm. 60, 17-23. https://doi.org/10.1016/j.ejpb.2004.11.010
  22. Lukacsko, E. J., Walters, E. I., Cullen, R., Niecestro, L. and Friedhoff, T. (2004) Effi cacy of once-daily extended-release lovastatin as compared to immediate-release lovastatin in patients with hypercholesterolemia. Curr. Med. Res. Opinion. 20, 13-18. https://doi.org/10.1185/030079903125002612
  23. Martin, P. D., Warwick, M. J., Dane, A. L., Hill, S. J., Giles, P. B., Phillips, P. J. and Lenz, E. (2003) Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin. Ther. 25, 2822-2835. https://doi.org/10.1016/S0149-2918(03)80336-3
  24. McClelland, G. A., Stubbs, R. J., Fix, J. A., Pogany, S. A. and Zentner, G. M. (1991) Enhancement HMG-CoA reductase inhibitor effi cacy through administration of a controlled-porosity osmotic pump dosage form. Pharm. Res. 8, 873-876. https://doi.org/10.1023/A:1015899328105
  25. Nishio, S., Watanabe, H., Kosuge, K., Uchida, S., Hayashi, H. and Ohashi, K. (2005) Interaction between amlodipine and simvastatin in patients with hypercholesterolemia and hypertension. Hypertens. Res. 28, 223-227. https://doi.org/10.1291/hypres.28.223
  26. Pedersen, T. R. and Tobert, J. A. (2004) Simvastatin: a review. Expert Opin. Pharmacother. 5, 2583-2596. https://doi.org/10.1517/14656566.5.12.2583
  27. Prueksaritanont, T., Qiu, Y., Mu, L., Michel, K., Brunner, J., Richards, K. M. and Lin, J. H. (2005) Interconversion pharmacokinetics of simvastatin and its hydroxy acid in dogs: effects of gemfi brozil. Pharm. Res. 22, 1101-1109. https://doi.org/10.1007/s11095-005-6037-2
  28. Shu, X. Z., Zhu, K. J. and Song, W. (2001) Novel pH sensitive citrate crosslinked chitosan fi lm for drug controlled release. Int. J. Pharm. 212, 19-28. https://doi.org/10.1016/S0378-5173(00)00582-2
  29. Singh, R. P., Gupta, R. C. and Singh, S. K. (2010) Interspecies comparison of the pharmacokinetics and oral bioavailability of 99-357, a potent synthetic trioxane antimalarial compound. Eur. J. Pharm. Sci. 41, 312-319. https://doi.org/10.1016/j.ejps.2010.06.013
  30. Sun, J. X., Niecestro, R., Phillips, G., Shen, J., Lukacsko, P. and Friedhoff, L. (2002) Comparative pharmacokinetics of lovastatin extended-release tablets and lovastatin immediate-release tablets in humans. J. Clin. Pharmacol. 42, 198-204. https://doi.org/10.1177/00912700222011111
  31. Thielemann, A. M., Manquez, N., Pinilla, E., Gai, M. N., Romero, P., Arancibia, A. and Chavez, H. (1996) Chronopharmacokinetics of theophylline administered as a controlled-release tablet. Int. J. Clin. Pharmaco Ther. 34, 130-133.
  32. Tobert, J. A. (1987) New developments in lipid-lowering therapy: the role of inhibitors of hydroxymethylglutaryl-coenzyme A reductase. Circulation 76, 534-538. https://doi.org/10.1161/01.CIR.76.3.534
  33. Vickers, S., Duncan, C. A., Chen, I. W., Rosegay, A. and Duggan, D. E. (1990a) Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug Metab. Dispos. 18, 138-145.
  34. Vickers, S., Duncan, C. A., Vyas, K. P., Kari, P. H., Arison, B., Prakash, S. R., Ramjit, H. G., Pitzenberger, S. M., Stokker, G. and Duggan, D. E. (1990b) In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase. Drug Metab. Dispos. 18, 476-483.
  35. Wikstrand, J., Andersson, B., Kendall, M. J., Stanbrook, H. and Klibaner, M. (2003) Pharmacokinetic considerations of formulation: extended-release metoprolol succinate in the treatment of heart failure. J. Cardiovasc. Pharmacol. 41, 151-157. https://doi.org/10.1097/00005344-200302000-00001
  36. Woo, J. S., Yi, H. G., Chi, M. H., Ryu, J. K., Jung, S. Y. and Kim, Y. I. (2005) Sustained release formulation for oral administration of HMG-COA reductase inhibitor and method for the preparation thereof, PCT WO 2005097194.