암로디핀이 레파그리니드의 약물동태에 미치는 영향

Effects of Amlodipine on the pharmacokinetics of Repaglinide

  • 최동현 (조선대학교 의과대학, 조선대학교 약학대학) ;
  • 최준식 (조선대학교 의과대학, 조선대학교 약학대학)
  • Choi, Dong-Hyun (College of Pharmacy, College of Medicine, Chosun University) ;
  • Choi, Jun-Shik (College of Pharmacy, College of Medicine, Chosun University)
  • 투고 : 2011.06.22
  • 심사 : 2011.08.30
  • 발행 : 2011.09.30

초록

암로디핀과 레파그리니드의 병용은 당뇨병의 합병증으로인한 고혈압 유발 시 병용 처방될 수 있다. 암로디핀과 레파그리니드의 약동학적 상호작용 연구를 위하여 암로디핀 (0.1 및 0.4 mg/kg) 과 레파그리니드를 흰 쥐에 경구(0.5 mg/kg) 및 정맥 (0.2 mg/kg) 투여하여 연구를 실시하였다. 암로디핀이 cytochrome P450 (CYP) 3A4 활성과 P-glycoprotein (P-gp)의 활성에 미치는 영향도 평가하였다. 암로디핀의 CYP3A4의 50% 효소활성억제는 $9.1{\mu}M$ 이었다. 암로디핀은 P-gp의 활성에는 영향을 미치지 않았다. 암로디핀 (0.4 mg/kg)은 레파그리니드의 혈장곡선하면적(AUC)과 최고혈장농도 ($C_{max}$)를 40.2% 와 22.2% 각각 유의성 (p < 0.05)있게 증가시켰다. 따라서, 레파그리니드의 상대적생체이용률 (RB)은 암로디핀과 병용투여 시 1.18-1.40 배 증가되었으며, 또한 레파그리니드의 절대적생체이용률(AB)은 대조군과 비교하여 41.0% 유의성 있게 증가되었다. 경구 투여 시와는 대조적으로, 암로디핀은 정맥 내로 투여된 레파그리니드에서는 약동학적 파라미터에 어떤 영향도 미치지 않았다. 따라서 암로디핀이 레파그리니드의 생체이용률을 증가시킨 것은 신장배설 감소 또는 P-gp 활성억제 보다는 암로디핀이 소장 또는 간장에서 CYP3A4을 억제시켰기 때문으로 사료된다. 암로디핀과 레파그리니드의 병용투여 시 레파그리니드의 용량을 조절하는 것이 안전하다고 사료된다.

키워드

참고문헌

  1. Kungys G, Naujoks H, Wanner C. Pharmacokinetics of amlodipine in hypertensive patients undergoing haemodialysis. Eur J Clin Pharmacol 2003; 59: 291-295. https://doi.org/10.1007/s00228-003-0620-4
  2. Abernethy DR. Pharmacokinetics and Pharmacodynamics of amlodipine. Cardiology 1992; 80: 31-36. https://doi.org/10.1159/000175050
  3. Meredith PA, Elliott HL. Clinical pharmacokinetics of amlodipine. Clin Pharmacokinet 1992; 22: 22-31. https://doi.org/10.2165/00003088-199222010-00003
  4. Nishio S, Watanabe H, Kosuge K, et al., Interaction between amlodipine and simvastatin in patients with hypercholesterolemia and hypertension. Hypertens Res 2005; 28: 223-227. https://doi.org/10.1291/hypres.28.223
  5. Kim KA, Park PW, Park JY. Effect of cytochrome P450 3A5*3 genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects. Chirality 2009; 21: 485-491. https://doi.org/10.1002/chir.20588
  6. Darvari R, Boroujerdi M. Concentration dependency of modulatory effect of amlodipine on P-glycoprotein efflux activity of doxorubicin - a comparison with tamoxifen. J Pharm Pharmacol 2004; 56: 985-991. https://doi.org/10.1211/0022357043941
  7. Harmsze AM, Robijns K, van Werkum JW, et al., The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response. Thromb Haemost 2010; 103: 920-925. https://doi.org/10.1160/TH09-08-0516
  8. El-Houssieny BM, Wahman LF, Arafa NM. Bioavailability and biological activity of liquisolid compact formula of repaglinide and its effect on glucose tolerance in rabbits. Biosci Trends 2010; 4: 17-24.
  9. Marbury TM, Ruckle JL, Hatorp V, et al., Pharmacokinetic of repaglinide in subjects with renal impairment. Clin Pharmacol Ther 2000; 67: 7-15. https://doi.org/10.1067/mcp.2000.103973
  10. Hatorp V, Won-Chin H, Strange P. Repaglinide pharmacokinetic in healthy young adult and eldery subjects. Clin Ther 1999; 21: 702-710. https://doi.org/10.1016/S0149-2918(00)88321-6
  11. Gromada J, Dissing S, Kofod H, et al., Effects of the hypoglycaemic drugs repaglinide and glibenclamide on ATP-sensitive potassium-channels and cytosolic 113 calcium levels in beta TC3 cells and rat pancreatic beta cells. Diabetologia 1995; 38: 1025-1032. https://doi.org/10.1007/BF00402171
  12. Ruzilawati AB, Wahab MS, Imran A, et al., Method development and validation of repaglinide in human plasma by HPLC and its application in pharmacokinetic studies. J Pharm Biomed Anal 2007; 43: 1831-1835. https://doi.org/10.1016/j.jpba.2006.12.010
  13. Culy JR, Jarvis B. Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus. Drugs 2001; 61: 1625-1660. https://doi.org/10.2165/00003495-200161110-00008
  14. Bidstrup TB. Björnsdottir, I., Sidelmann, U. G., et al., CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. Br J Clin Pharmacol 2003; 56: 305-314. https://doi.org/10.1046/j.0306-5251.2003.01862.x
  15. Bauer E, Beschke K, Ebner T, et al., Biotransformation of [$^{14}C$] repaglinide in human, cynomolgus monkey, dog, rabbit, rat and mouse. Diabetologia 1997; 1: 326-332.
  16. Chang C, Bahadduri PM, Polli JE, et al., Rapid identification of P-glycoprotein substrates and inhibitors. Drug Metab Dispos 2006; 34: 1976-1984. https://doi.org/10.1124/dmd.106.012351
  17. Kajosaari L, Niemi M, Neuvonen M, et al., Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin Pharmacol Ther 2005; 78: 388-399. https://doi.org/10.1016/j.clpt.2005.07.005
  18. Crespi CL, Miller VP, Penman BW. Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450. Anal Biochem 1997; 248: 188-190. https://doi.org/10.1006/abio.1997.2145
  19. Han CY, Cho KB, Choi HS, et al., Role of FoxO1 activation in MDR1 expression in adriamycin-resistant breast cancer cells. Carcinogenesis 2008; 29: 1837-1844. https://doi.org/10.1093/carcin/bgn092
  20. Gomes MB, Giannella-Neto D, Faria M, et al., Estimating cardiovascular risk in patients with type 2 diabetes: a national multicenter study in Brazil. Diabetol Metab Syndr 2009; 1: 22-28. https://doi.org/10.1186/1758-5996-1-22
  21. Gonzalez FJ. Cytochrome P450 in humans. In: Schenkman JB, Grein H, editors. Cytochrome P450: handbook of experimental pharmacology. 1993; Vol. 105: Berlin: Springer- Verlag.
  22. Li AP, Kaminski DL, Rasmussen A. Substrates of human hepatic cytochrome P450 3A4. Toxicology 1995; 104: 1-8. https://doi.org/10.1016/0300-483X(95)03155-9
  23. Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol 1992; 22: 1-21. https://doi.org/10.3109/10408449209145319
  24. Kelly PA, Wang H, Napoli KL, et al., Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4. Eur. J. Drug Metab Pharmacokinet 1999; 24: 321-328. https://doi.org/10.1007/BF03190040
  25. Bogaards JJ, Bertrand M, Jackson P, et al., Determining the best animal model for human cytochrome P450 activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey and man. Xenobiotica 2000; 30: 1131-1152. https://doi.org/10.1080/00498250010021684
  26. 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.
  27. Lewis DFV. Cytochrome P450. Substrate specificity and metabolism. In: Cytochromes P450. Structure, Function, and Mechanism. Taylor & Francis: Bristol, 1996; 122- 123.
  28. Cao X, Gibbs ST, Fang L, et al., Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model. Pharm Res 2006; 23: 1675-1686. https://doi.org/10.1007/s11095-006-9041-2
  29. 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
  30. 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
  31. 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
  32. 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
  33. Kivisto KT, Bookjans G, Formm MF, et al., Expression of CYP3A4, CYP3A5 and CYP3A7 in human duodenal tissue. Br. J Clin Pharmacol 1996; 42: 387-389.
  34. Zhang QY, Dunbar D, Ostrowska A, et al., Characterization of human small intestinal cytochromes P-450. Drug Metab Dispos 1999; 27: 804-809.
  35. Niemi M, Neuvonen PJ, Kivisto KT. The cytochrome P450 3A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther 2001; 70: 58-65. https://doi.org/10.1067/mcp.2001.116511
  36. Niemi M, Backman JT, Neuvonen M, et al., Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and Pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 2003; 46: 347-351. https://doi.org/10.1007/s00125-003-1034-7