Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Effects of Atorvastatin on the Pharmacokinetics of Nicardipine after Oral and Intravenous Administration in Rats

  • Choi, Jun-Shik (Pharmaceutic Division, College of Pharmacy, Chosun University) ;
  • Ha, Sung-Il (Cardiovascular Division, College of Medicine, Chosun University) ;
  • Choi, Dong-Hyun (Cardiovascular Division, College of Medicine, Chosun University)
  • Received : 2010.03.13
  • Accepted : 2010.04.19
  • Published : 2010.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

The aim of this study was to investigate the effect of atrovasatatin on the pharmacokinetics of nicardipine after oral and intravenous administration of nicardipine to rats. Nicardipine was administered orally (12 mg/kg) or intravenously (i.v., 4 mg/kg) without or with oral administration of atrovasatatin (0.3 or 1.0 mg/kg) to rats. The effect of atorvastatin on the P-glycoprotein (P-gp) as well as CYP3A4 activity was also evaluated. Atorvastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of 48 ${\mu}M$. Compared to the controls (nicardipine alone), the area under the plasma concentration-time curve (AUC) of nicardipine was significantly (1.0 mg/kg, p<0.05) greater by 16.8-45.4%, and the peak plasma concentration ($C_{max}$) was significantly (1.0 mg/kg, p<0.05) higher by 28.0% after oral administration of nicardipine with atorvastatin, respectively. Consequently, the relative bioavailability (R.B.) of nicardipine was increased by 1.17- to 1.45-fold and the absolute bioavailability (A.B.) of nicardipine with atrovasatatin was significantly greater by 16.7-20.9% compared to that of the controls (14.3%). Compared to the i.v. control, atrovasatatin did not significantly change pharmacokinetic parameters of i.v. administration nicardipine. The enhanced oral bioavailability of nicardipine by atorvastatin suggests that CYP3A subfamily-mediated metabolism were inhibited in the intestine and/or in the liver rather than P-gp-mediated efflux of nicardipine. Based on these results, modification of nicardipine of dosage regimen is required in the patients. Human studies are required to prove the above hypothesis.

Keywords

References

  1. Azie, N. E., Brater, D. C., Becker, P. A., Jones, D. R. and Hall, S. D. (1998). The interaction of diltiazem with lovastatin and pravastatin. Clin. Pharmacol. Ther. 64, 369-377. https://doi.org/10.1016/S0009-9236(98)90067-4
  2. Benet, L. Z., Cummins, C. L. and Wu, C. Y. (2003). Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data. Curr. Drug Metab. 4, 393-398. https://doi.org/10.2174/1389200033489389
  3. Choi, D. H., Chang, K. S., Hong, S. P. and Choi, J. S. (2008). Effect of atrovastatin on intravenous and oral pharmacokinetics of verapamil in rats. Biopharm. Drug Dispos. 29, 45-50. https://doi.org/10.1002/bdd.582
  4. Choi, J. S., Piao, Y. J. and Han, H. K. (2006). Phatmacokinetics interaction between fluvastatin and diltiazem in rats. Biopharm. Drug Dispos. 27, 437-441. https://doi.org/10.1002/bdd.521
  5. Cummins, C. L., Jacobsen, W. and Benet, L. Z. (2002). Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J. Pharmacol. Exp. Ther. 300, 1036-1045. https://doi.org/10.1124/jpet.300.3.1036
  6. Doppenschmitt, S., Spahn-Langguth, H., Rerardh, C. G. and Langguth, P. (1999). Role of P-glycoprotein-mediated secretion in aborptive drug permeability: an approach using passive membrane permeability and affinity to P-glycoprotein. J. Pharm. Sci. 88, 1067-1072. https://doi.org/10.1021/js980378j
  7. Eastwood, R. J., Galustian, C., Bhamra, R. K. and Holt, D. W. (1990). High-performance liquid chromatographic method for the measurement of nicardipine in plasma or serum. J. Chromatogr. 530, 463-468. https://doi.org/10.1016/S0378-4347(00)82351-8
  8. Graham, D. J., Dow, R. J., Freedman, D., Mroszczak, E. and Ling, T. (1984). Pharmacokinetics of nicardipine following oral and intravenous administration in man. Postgrad. Med. J. 4, 7-10.
  9. Graham, D. J., Dow, R. J., Hall, D. J., Alexander, O. F., Mroszczak, E. J. and Freedman, D. (1985). The metabolism and pharmacokinetics of nicardipine hydrochloride in man. Br. J. Cli. Pharmacol. 1, 23-28.
  10. Guengerich, F. P. (1991). Reactions and significance of cytochrome P-450 enzymes. J. Biol. Chem. 266, 10019-10022.
  11. Guengerich, F. P., Martin, M. V., Beaune, P. H., Kre-mers, P., Wolff, T. and Waxman, D. J. (1986). Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J. Biol. Chem. 261, 5051-5060.
  12. Higuchi, S. and Shiobara, Y. (1980). Metabolic fate of nicardipine hydrochloride, a new vasodilator, by various species in vitro. Xenobiotica 10, 889-896. https://doi.org/10.3109/00498258009033822
  13. Holtzman, C. W., Wiggins, B. S. and Spinler, S. A. (2006). Role of P-glycoprotein in statin drug interaction. Pharmacotherapy 26, 1601-1607. https://doi.org/10.1592/phco.26.11.1601
  14. Hu, Y. P., Chapey, C. and Robert, J. (1996). Relationship between the inhibition of azidopine binding to P-glycoprotein by MDR modulators and their efficiency in restoring doxorubicin intracellular accumulation. Cancer Lett. 109, 203-209. https://doi.org/10.1016/S0304-3835(96)04454-0
  15. Hysing, E. S., Chelly, J. E., Doursout, M. F., Hartley, C. and Merin, R. G. (1986). Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. Nicardipine and isoflurane. Anaesthesiology 65, 385-391. https://doi.org/10.1097/00000542-198610000-00007
  16. Kaminsky, L. S. and Fasco, M. J. (1991). Small intestinal cytochromes P450. Crit. Rev. Toxicol. 21, 407-422. https://doi.org/10.3109/10408449209089881
  17. Kishi, Y., Okumura, F. and Furuya, H. (1984). Haemodynamic effects of nicardipine hydrochloride. Studies during its use to control acute hypertension in anaesthetized patients. Br. J. Anaesth. 56, 1003-1007. https://doi.org/10.1093/bja/56.9.1003
  18. Kolars, J. C., Schmiedlin-Ren, P., Schuetz, J. D., Fang, C. and Watkins, P. B. (1992). Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J. Clin. Invest. 90, 1871-1878. https://doi.org/10.1172/JCI116064
  19. Lea, A. P. and McTavish, D. (1997). Atrovastatin: a review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. Drugs 53, 828-847. https://doi.org/10.2165/00003495-199753050-00011
  20. Lennernas, H. (2003). Clinical pharmacokinetics of atrovastatin. Clin. Pharmacokinet. 42, 1141-1160. https://doi.org/10.2165/00003088-200342130-00005
  21. Mousa, O., Brater, D. C., Sunblad, K. J. and Hall, S. D. (2000). The interaction of diltiazem with simvastatin. Clin. Pharmacol. Ther. 67, 267-274. https://doi.org/10.1067/mcp.2000.104609
  22. Saeki, T., Ueda, K., Tanigawara, Y., Hori, R. and Komano, T. (1993). P-glycoprotein-mediated transcellular transport of MDR-reversing agents. FEBS Lett. 324, 99-102. https://doi.org/10.1016/0014-5793(93)81540-G
  23. Shitara, Y. and Sugiyama, Y. (2006). Pharmacokinetics and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interaction and interindixidual differences in transporter and metabolic enzyme function. Pharmacol. 112, 71-105.
  24. Van Swieten, P. A., Hansson, L. and Epstein, M. (1997). Slowly acting calcium antagonists and their merits. Blood Press 6, 78-90. https://doi.org/10.3109/08037059709061803
  25. Wacher, V. J., Salphati, L. and Benet, L. Z. (2001). Active secretion and enterocytic drug metabolism barriers to drug absorption. Adv. Drug Deliv. Rev. 46, 89-102. https://doi.org/10.1016/S0169-409X(00)00126-5
  26. Wang, E. J., Casciano, C. N., Clement, R. P. and Johnson, W. W. (2000). Two transport binding sites of P-glycoprotein are unequal yet contingent: initial rate kinetic analysis by ATP hydrolysis demonstrates intersite dependence. Biochim. Biophys. Acta. 1481, 63-74. https://doi.org/10.1016/S0167-4838(00)00125-4