Korean Journal of Clinical Pharmacy (한국임상약학회지)

Korean College Of Clinical Pharmacy (한국임상약학회)
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Effects of Ticlopidine on the Bioavailability and Pharmacokinetics of Nicardipine after Oral and Intravenous Administration

티크로피딘이 니칼디핀의 생체이용률 및 약물동태에 미치는 영향

  • Moon, Hong-Seop (College of Pharmacy, Mokpo National University) ;
  • Choi, Jun-Shik (College of Pharmacy & Graduate School of Clinical Pharmacy, Chosun University) ;
  • Bang, Joon-Seok (College of Pharmacy & Graduate School of Clinical Pharmacy, Chosun University)
  • 문홍섭 (국립목포대학교 약학대학) ;
  • 최준식 (조선대학교 약학대학 & 임상약학대학원) ;
  • 방준석 (조선대학교 약학대학 & 임상약학대학원)
  • Received : 2011.12.30
  • Accepted : 2012.01.30
  • Published : 2012.03.31
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Abstract

항혈소판제인 티크로피딘과 항고혈압제인 니칼디핀과의 약동학적 상호작용 연구를 위하여 티크로피딘 (3 또는 10 mg/kg)과 니칼디핀의 경구 (4 mg/kg) 및 정맥 (12 mg/kg) 투여하여 본 연구를 시행하였다. 연구방법: 티크로피딘이 cytochrome P450 (CYP) 3A4 활성과 P-glycoprotein (P-gp)의 활성에 미치는 영향도 평가하였다. 결 과: 티크로피딘과 니칼디핀의 병용투여 시 티크로피딘이 니칼디핀의 약물동태 파라미터에 미치는 결과는 다음과 같다. 티크로피딘은 CYP3A4 효소의 활성을 저해 하였으나 P-gp활성에는 영향을 미치지 못하였다. 니칼디핀의 혈중농도곡선하면적 (AUC)는 대조군에 비해 티크로피딘 10 mg/kg 병용투여군에서 유의성 (p < 0.05)있게 증가되었다. 상대적 생체이용률 (RB)은 티크로피딘 병용투여군에서 115-143%로 증가하였다. 결 론: 본 논문에서 흰쥐에 티크로피딘과 니칼디핀을 병용경구투여 시 니칼디핀의 생체이용률 (bioavailability)이 유의성 (p < 0.05)있게 증가된 것은 티크로피딘이 대사효소인 CYP3A4를 억제하여 소장과 간장에서 초회통과효과 (first-pass metabolism)를 감소 시켰기 때문인 것으로 사료된다. 본 실험결과를 토대로 인체에서 티크로피딘과 니칼디핀의 상호작용을 검토한 후 투여용량을 조절하는 것이 바람직하다고 사료된다.

Keywords

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: 1003-1007. 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. Nicardipine and isoflurane. Anaesthesiology 1986; 65: 385-391. https://doi.org/10.1097/00000542-198610000-00007
  3. Van Swieten PA, Hansson L, Epstein M. Slowly acting calcium antagonists and their merits. 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 Cli. Pharmacol 1985; 1: 23-28.
  6. Higuchi S, Shiobara Y. Metabolic fate of nicardipine hydrochloride, a new vasodilator, by various species in vitro. Xenobiotica 1980: 10, 889-896. https://doi.org/10.3109/00498258009033822
  7. Guengerich FP. Reactions and significance of cytochrome P- 450 enzymes. J Biol Chem 1991; 266: 10019-10022.
  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: 5051-5060.
  9. Hu YP, Chapey C, Robert J. Relationship between the inhibition of azidopine binding to P-glycoprotein by MDR modulators and their efficiency in restoring doxorubicin intracellular accumulation. Cancer Lett 1996; 109: 203-209. https://doi.org/10.1016/S0304-3835(96)04454-0
  10. 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. Biochim Biophys Acta 2000; 1481: 63-74. https://doi.org/10.1016/S0167-4838(00)00125-4
  11. Saltiel E, Ward A. Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutics efficacy in platelet-dependent disease states. Drugs 1987; 34: 222-262. https://doi.org/10.2165/00003495-198734020-00003
  12. Gent M, Blakely JA, Easton JD, et al., The Canadian American ticlopidine study (CATS) in thromboembolic stroke. Lancet 1989; 1: 1215-1220.
  13. Hass, W. k., Easton, J. D., Adams, H. P., et al., A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501-507. https://doi.org/10.1056/NEJM198908243210804
  14. Janzon L, Bergqvist D, Boberg J, et al., Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. J Intern Med 1990; 227: 301-308. https://doi.org/10.1111/j.1365-2796.1990.tb00164.x
  15. Haynes RB, Sandler RS, Larson EB, et al., A critical appraisal of ticlopidine, a new antiplatelet agent. Effectiveness and clinical indications for prophylaxis of atherosclerotic events. Arch Intern Med 1998; 152: 1376- 1380.
  16. Ito MK, Smith AR, Lee ML. Ticlopidine: a new platelet aggregation inhibitors. Clin Pharm 1992; 11: 603-617.
  17. Verhaeghe R. Prophylactic antiplatelet therapy in peripheral arterial disease. Drugs 1991; 42: 51-57.
  18. Solomon DH, Hart RG. Antithrombotic therapies for stroke prevention. Curr Opin Neuro 1994; 7: 48-53. https://doi.org/10.1097/00019052-199402000-00009
  19. Buur T, Larsson R, Berglund U, et al., Pharmocokinetics and effect of ticlopidine on platelet aggregation in subjects with normal and impaired renal function. J Clin Pharmacol 1997; 37: 108-115. https://doi.org/10.1002/j.1552-4604.1997.tb04768.x
  20. Ko JW, Desta Z, Soukhova NV, et al., In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C9 and CYP2D6. Br J Clin Pharmacol 2000; 49: 343-351.
  21. Gidal BE, Sorkness CA, McGill KA, et al., Evaluation of a potential enantioselective interaction between ticlopidine and warfarin in chronically anticoagulated patients. Ther Drug Monit 1995; 17: 33-38. https://doi.org/10.1097/00007691-199502000-00006
  22. Shah J, Fratis A, Ellis D, et al., Effect of food and antacid on absorption of orally administered ticlopidine hydrochloride. J Clin Pharmacol 1990; 30: 733-736. https://doi.org/10.1002/j.1552-4604.1990.tb03635.x
  23. Eastwood RJ, Galustian C, Bhamra RK, et al., Highperformance liquid chromatographic method for the measurement of nicardipine in plasma or serum. J Chromatogr 1990; 530: 463-468. https://doi.org/10.1016/S0378-4347(00)82351-8
  24. Kaminsky LS, Fasco MJ. Small intestinal cytochromes P450. Crit Rev Toxicol 1991; 21: 407-422 .
  25. Cummins CL, Jacobsen W, Benet LZ. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 2002; 300: 1036-1045. https://doi.org/10.1124/jpet.300.3.1036
  26. Benet LZ, Cummins CL, Wu CY. Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data. Curr Drug Metab 2003; 4: 393-398. https://doi.org/10.2174/1389200033489389
  27. Saeki T, Ueda K, Tanigawara Y, et al., P-glycoproteinmediated transcellular transport of MDR-reversing agents. FEBS Lett 1993; 324: 99-102. https://doi.org/10.1016/0014-5793(93)81540-G
  28. Wacher VJ, Salphati L, Benet LZ. Active secretion and enterocytic drug metabolism barriers to drug absorption. Adv Drug Deliv Rev 2001; 46: 89-102. https://doi.org/10.1016/S0169-409X(00)00126-5
  29. Kolars JC, Schmiedlin-Ren P, Schuetz JD, et al., Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 1992; 90: 1871-1878. https://doi.org/10.1172/JCI116064
  30. Lea AP, McTavish D. Atorvastatin: a review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. Drugs 1997; 53: 828-847. https://doi.org/10.2165/00003495-199753050-00011
  31. Holtzman CW, Wiggins BS, Spinler SA. Role of Pglycoprotein in statin drug interaction. Pharmacotherapy 2006; 26: 1601-1607. https://doi.org/10.1592/phco.26.11.1601
  32. Choi DH, Chang KS, Hong SP, et al., Effect of atorvastatin on intravenous and oral pharmacokinetics of verapamil in rats. Biopharm Drug Dispos 2008; 29: 45-50 https://doi.org/10.1002/bdd.582