Korean Journal of Clinical Pharmacy (한국임상약학회지)

Korean College Of Clinical Pharmacy (한국임상약학회)
권호 표지

Pharmacokinetic Interaction between Ticlopidine and Nimodipine in Rats

티크로피딘과 니모디핀과의 약동학적 상호작용

  • Kim, Yang-Woo (National Health Insurance Corporation, College of Pharmacy, Chosun University) ;
  • Choi, Jun-Shik (National Health Insurance Corporation, College of Pharmacy, Chosun University)
  • 김양우 (국민건강보험공단, 조선대학교 약학대학) ;
  • 최준식 (국민건강보험공단, 조선대학교 약학대학)
  • Received : 2010.09.30
  • Accepted : 2010.11.28
  • Published : 2010.12.31
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Abstract

The purpose of this study was to investigate the effect of ticlopidine on the pharmacokinetics of nimodipine in rats. Pharmacokinetic parameters of nimodipine were determined in rats after oral administration of nimodipine (16 mg/kg) with or without ticlopidine (3 or 10 mg/kg). Ticlopidine inhibited cytochrome P450 (CYP)3A4 activity. Ticlopidine significantly (p<0.05, 10 mg/kg) increased the area under the plasma concentration-time curve (AUC) of nimodipine and ticlopidine significantly (p<0.05, 10 mg/kg) prolonged the terminal half-life ($t_{1/2}$) of nimodipine. Ticlopidine significantly (p<0.05, 10 mg/kg) decreased the total body clearance ($CL_t$). The absolute bioavailability (AB%) and relative bioavailability (RB%) of nimodipine by presence of ticlopidine were increased by 14% and by 42%, respectively, compared to the control. Based on these results, the increased bioavailability of nimodipine might be due to inhibition of the metabolizing enzyme cytochrome P450 (CYP)3A4 in the liver or intestinal mucosa and/or reducing total body clearance by ticlopidine.

Keywords

References

  1. Scholz H. Pharmacological aspects of calcium channel blockers. Cardiovasc. Drugs Ther 1997; 10: 869-872. https://doi.org/10.1007/BF00051613
  2. Epstein M, Loutzenhister RD. Effects of calcium antagonists on renal hemodynamics. Am J Kidney Dis 1990; 16: 10-14.
  3. Kazda S, Garthoff B, Krause HP, et al., Cerebrovascular effects of the calcium antagonistic dihydropyridine derivative nimodipine in animal experiments. Arzneimittelforschung 1982; 32: 331-338.
  4. Maruhn D, Siefert HM, Weber H, et al., Pharmacokinetics of nimodipine. I. communication: absorption, concentration in plasma and excretion after single administration of [$^{14}C$] nimodipine in rat, dog and monkey. Arzneimittelforschung 1985; 35: 1781-1786.
  5. Suwelack D, Weber H, Maruhn D. Pharmacokinetics of nimodipine, II. communication: absorption, concentration in plasma and excretion after single administration of [$^{14}C$] nimodipine in rat, dog and monkey. Arzneimittelforschung 1985; 35: 1787-1794.
  6. Ramsch KD, Ahr G, Tettenborn D, et al., Overview on pharmacokinetics of nimodipine in healthy volunteer and in patients with subarachnoid hemorrhage. Neurochirurgia 1985; 28: 74-78.
  7. Scherling D, Buhner K, Krause HP, et al., Biotransformation of nimodipine in rat, dog and monkey. Arzneimittelforschung 1991; 41: 392-398.
  8. Guengerich FP, Brian WR, Iwasaki M, et al., Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrom P-450IIIA4. J Med Chem 1991; 34: 1834-1844.
  9. Fuhr U, Maier-Bruggemann A, Blume H, et al., Grapefruit juice increases oral nimodipine bioavailability. Int J Clin Pharmacol Ther 1998; 36: 126-132.
  10. Zhang L, Liu XD, Xie L, et al., P-glycoprotein restricted transport of nimodipine across blood-brain barrier. Acta Pharmacol Sin 2003; 24: 903-906.
  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 Wk, Easton JD, Adams HP, et al., A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Eng 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. Cur Opin Neurol 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. Qian M, Gallo JM. High-perfomance liquid chromatographic determinination of the calcium channel blocker nimodipine in monkey plasma. J Chromatogr 1992; 578: 316-320. https://doi.org/10.1016/0378-4347(92)80432-P
  24. Mc Donnell CG, Shorten G, Van Pelt FN. Effect of atorvastatin and fluvastatin on the metabolism of midazolam by cytochrome P450 in vitro. Anaesthesia 2005; 60: 747-753. https://doi.org/10.1111/j.1365-2044.2005.04110.x
  25. Choi JS, Burm JP. Enhanced nimodipine bioavailability after oral administration of nimodipine with morin, flavonoid, in rabbits. Arch Pharm Res 2006; 29: 333-338. https://doi.org/10.1007/BF02968580
  26. Piao YJ, Choi JS. Effects of fluvastatin on the pharmacokinetics of diltiazem and its metabolite in rats. Yakhak Hoeji 2006; 50: 118-123.
  27. Choi DH, Lee IG, Choi JS. Pharmacokinetic interaction between fluvastatin and nicardipine. Kor J Clin Pharm 2007; 17: 65-69.