Korean Journal of Clinical Pharmacy (한국임상약학회지)

Korean College Of Clinical Pharmacy (한국임상약학회)
권호 표지

Pharmacokinetic Interaction between Simvastatin and Nicardipine

심바스타틴과 니카르디핀과의 약동학적 상호작용

  • Received : 2009.03.18
  • Accepted : 2009.04.07
  • Published : 2009.06.30
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Abstract

The aim of this study was to investigate the effect of simvastatin on the pharmacokinetics of nicardipine in rats. Pharmacokinetic parameters of nicardipine were determined after an oral administration of nicardipine (12 mg/kg) to rats coadministered with simvastatin (0.3 and 1.0 mg/kg). Compared with the control (given nicardipine alone), coadministration of simvastatin (1.0 mg/kg) significantly (p<0.05) increased the area under the plasma concentration (AUC) and peak plasma concentration ($C_{max}$) of nicardipine. The relative bioavailability (RB%) of nicardipine increased from 1.19- to 1.48-fold. However there were no significant changes in $t_{max}$, and $t_{1/2}$ of nicardipine. The enhanced oral bioavailability of nicardipine might be due to an inbition of cytochrom P450 3A mediated-metabolism of nicardipine in the intestine and in the liver by simvastatin. Based on these results, the concurrent use of simvastatin significantly enhanced the oral exposure of nicardipine in rats. The dosage regimen of nicardipine should be taken into consideration for potential drug interaction when combined with simvastatin in clinics.

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References

  1. Kishi Y, Okumura F, Furuya H. Haemodynamic effects of nicardipine hydrochloride. Studies during its use to control acute hypertension in anaesthetized patients. Br J Anaesth 1984; 56: 1003-7. https://doi.org/10.1093/bja/56.9.1003
  2. Hysing ES, Chelly JE, Doursout MF, et al. Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. III. Nicardipine and isoflurane. Anaesthesiology 1986; 65: 385-91. https://doi.org/10.1097/00000542-198610000-00007
  3. Van Swieten PA, Hansson L, Epstein M. Blood Press 1997; 6: 78-90. https://doi.org/10.3109/08037059709061803
  4. Graham DJ, Dow RJ, Freedman D, et al. Pharmacokinetics of nicardipine following oral and intravenous administration in man. Postgrad Med J 1984; 4: 7-10.
  5. Graham DJ, Dow RJ, Hall DJ, et al. The metabolism and pharmacokinetics of nicardipine hydrochloride in man. Br J Clin Pharmacol 1985; 1: 23-8.
  6. Higuchi S, Shiobara Y. Metabolic fate of nicardipine hydrochloride, a new vasodilator, by various species in vitro. Xenobiotica 1980; 10: 889-96. https://doi.org/10.3109/00498258009033822
  7. Guengerich FP. Reactions and significance of cytochrome P-450 enzymes. J Biol Chem 1991; 266: 10019-22.
  8. Guengerich FP, Martin MV, Beaune PH, et al. 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 1986; 261: 5051-60.
  9. Wang EJ, Casciano CN, Clement RP, et al. Two transport binding sites of P-glycoprotein are unequal yet contingent : initial rate kinetic analysis by ATP hydrolysis demonstrates intersite dependence, Biochem Biophys Acta 2000; 1481: 63-74. https://doi.org/10.1016/S0167-4838(00)00125-4
  10. Mauro VF, MacDonald JL. Simvastatin: a review of its pharmacology and clinical use. DICP 1991; 25: 257-64. https://doi.org/10.1177/106002809102500309
  11. Schectman G, Hiatt J. Dose-response characteristics of cholesterol-lowering drug therapies: implications for treatment. Ann Intern Med 1998; 125: 990-1000.
  12. Plosker GL, McTavish D. Simvastatin:a reappraisal of its pharmacology and therapeutic efficacy in hypercholesterolaemia. Drugs 1995; 50: 334-63. https://doi.org/10.2165/00003495-199550020-00009
  13. Lennernäs H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors: similarities and differences. Clin Pharmacokinet 1997; 32: 403-25. https://doi.org/10.2165/00003088-199732050-00005
  14. Prueksaritanout T, Gorham LM, ma B. In vivo metabolism of simvastatin in human: identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab Dispos 1997; 25: 1191-9
  15. Cohen LH, Van Leeuwen RE, Van Thiel GC et al. Equally potent inhibitors of cholesterol synthesis in human hepatocytes have distinguishable effects on different cytochrome P450 enzymes. Biopharm Drug Dispos 2000; 21: 353-64. https://doi.org/10.1002/bdd.249
  16. Kirchheiner J, Brockmoller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 2005; 77: 1-16. https://doi.org/10.1016/j.clpt.2004.08.009
  17. Maura VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 1993; 24: 195-202 https://doi.org/10.2165/00003088-199324030-00002
  18. Yeo KR, Yeo WW. Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes. Br J Clin Pharmacol 2001; 51: 461-70.
  19. Watanabe H, Kosuge K, Nishio S et al. Pharmacokinetic and pharmacodynamic interactions between simvastatin and diltiazem in patients with hypercholesterolemia and hypertension. Life Sci 2004; 76: 281-92. https://doi.org/10.1016/j.lfs.2004.06.022
  20. Wang EJ, Casciano CN, Clement RP, et al. HMG-Coa reductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein. Pharm Res 2001; 18: 800-806. https://doi.org/10.1023/A:1011036428972
  21. Eastwood RJ, Galustian C, Bhamra RK. High-performance liquid chromatographic method for the measurement of nicardipine in plasma or serum. J Chromatogr 1990; 530: 463-8. https://doi.org/10.1016/S0378-4347(00)82351-8
  22. Mc Donnell CG, Shorten G, Van Pelt FN. Effect of atorvastatin and simvastatin on the metabolism of midazolam by cytochrome P450 in vitro. Anaesthesia 2005; 60: 747-53. https://doi.org/10.1111/j.1365-2044.2005.04110.x
  23. Choi JS, Piao YJ, Han HK. Pharmacokinetic interaction between fluvastatin and diltiazem in rats. Biopharm Drug Dispos 2006; 27: 437-41. https://doi.org/10.1002/bdd.521
  24. Kim DH, Choi JS, Han HK, et al. Effect of atrovastatin on the Intravenous and Oral Pharmacokinetics of Verapamil in rats. Biopharm Drug Dispos 2008; 29: 45-50. https://doi.org/10.1002/bdd.582