Korean Journal of Clinical Pharmacy (한국임상약학회지)

Korean College Of Clinical Pharmacy (한국임상약학회)
권호 표지

Effects of Apigenin, an Antioxidant, on the Bioavailability and Pharmacokinetics of Etoposide

항산화제인 아피제닌이 에토포시드의 생체이용률 및 약동학에 미치는 영향

  • Received : 2011.03.04
  • Accepted : 2011.05.10
  • Published : 2011.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

에토포시드와 아피제닌의 약동학적 상호작용 연구를 위하여 아피제닌 (0.4, 2.0 또는 8 mg/kg)과 에토포시드의 경구(6 mg/kg) 및 정맥 (2 mg/kg) 투여 하여 본 연구를 실시하였다. 아피제닌이 cytochrome P450 (CYP) 3A4 활성과 P-glycoprotein (P-gp)의 활성에 미치는 영향도 평가하였다. 아피제닌의 CYP3A4의 50% 효소활성억제는 $1.8{\mu}M$ 이었다. 아피제닌은 MCF-7/ADR 세포의 로다마인-123 세포 축적을 증가 시키므로 P-gp를 억제시켰다. 아피제닌은 에토포시드의 혈장곡선하면적과 최고혈장농도 (AUC and $C_{max}$)를 유의성 있게 증가시켰으나, 에토포시드의 최고혈장농도 도달시간 ($T_{max}$)과 생물학적 반감기 ($t_{1/2}$)에는 영향을 미치지 않았다. 따라서, 아피제닌 존재하에 에토포시드의 절대적생체이용률 (AB)은 대조군과 비교하여 유의성있게 증가되었다. 경구투여시와는 대조적으로, 아피제닌은 정맥 내로 투여된 에토포시드에서는 약동학적 파라미터에 어떤 영향도 미치지 않았다. 따라서 아피제닌이 에토포시드의 생체이용률을 증가시킨 것은 아피제닌이 소장과 간장에서 CYP3A4을 억제 및 소장에서 P-gp를 억제 시켰기 때문으로 사료된다.

Keywords

References

  1. Stahelin HF, von Wartburg A. The chemical and biological route from podophyllotoxin glucoside to etoposide: Ninth Cain memorial award lecture. Cancer Res 1991; 51: 5-15.
  2. Clark PI, Slevin ML. The clinical pharmacology of etoposide and teniposide. Clin Pharmacokinet 1987; 12: 223-252. https://doi.org/10.2165/00003088-198712040-00001
  3. Wozniak AJ, Ross WE. DNA damage as a basis for 4'- demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-Dglucopyranoside) (etoposide) cytotoxicity. Cancer Res 1983; 43: 120-124.
  4. van Maanen JM, de Vries J, Pappie D. Cytochrome P- 450-mediated O-demethylation: a route in the metabolic activation of etoposide (VP-16-213). Cancer Res 1987; 47: 4658-4662.
  5. Relling MV, Nemec J, Schuetz EG, et al., Odemethylation of epipodophyllotoxins is catalyzed by human cytochrome P450 3A4. Mol Pharmacol 1994; 45: 352-358.
  6. Kawashiro T, Yamashita K, Zhao XJ, et al., A study on the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes. J Pharmacol Exp Ther 1998; 286: 1294- 1300.
  7. Leu BL, Huang JD. Inhibition of intestinal P-glycoprotein and effects on etoposide absorption. Cancer Chemother Pharmacol 1995; 35: 432-436. https://doi.org/10.1007/s002800050258
  8. Carcel-Trullols J, Torres-Molina F, Araico A, et al., Effect of cyclosporine A on the tissue distribution and pharmacokinetics of etoposide. Cancer Chemother Pharmacol 2004; 54: 153- 160.
  9. Keller RP, Altermatt HJ, Donatsch P, et al., Pharmacologic interactions between the resistance-modifying cyclosporine SDZ PSC 833 and etoposide (VP 16-213) enhance in vivo cytostatic activity and toxicity. Int J Cancer 1992; 51: 433- 438. https://doi.org/10.1002/ijc.2910510316
  10. Dixon RA, Steele CL. Flavonoids and isoflavonoids - a gold mine for metabolic engineering. Trends Plant Sci 1999; 4: 394-400. https://doi.org/10.1016/S1360-1385(99)01471-5
  11. Yin Y, Gong FY, Wu XX, et al., Anti-inflammatory and immunosuppressive effect of flavones isolated from Artemisia vestita. J Ethnopharmacol 2008; 120: 1-6. https://doi.org/10.1016/j.jep.2008.07.029
  12. Nafisi S, Hashemi M, Rajabi M. DNA Adducts with Antioxidant Flavonoids: Morin, Apigenin, and Naringin. DNA and Cell Biology 2008; 27: 1-10. https://doi.org/10.1089/dna.2008.1500
  13. Galati G, Moridani MY, Chan TS, et al., Peroxidative metabolism of apigenin and naringenin versus luteolin and quercetin: glutathione oxidation and conjugation. Free Radical Biology & Medicine. 2001; 30: 370-382. https://doi.org/10.1016/S0891-5849(00)00481-0
  14. Chuang CM, Monie A, Wu A, et al., Combination of apigenin treatment with therapeutic HPV DNA vaccination generates enhanced therapeutic antitumor effects. J Biomed Sci 2009; 16: 49-60. https://doi.org/10.1186/1423-0127-16-49
  15. Jeong GS, Lee SH, Jeong SN, et al., Anti-inflammatory effects of apigenin on nicotine- and lipopolysaccharidestimulated human periodontal ligament cells via heme oxygenase-1. Int Immunopharmacol 2009; 9: 1374-1380. https://doi.org/10.1016/j.intimp.2009.08.015
  16. Gates MA, Vitonis AF, Tworoger SS, et al., Flavonoid intake and ovarian cancer risk in a population-based case-control study. Int J Cancer 2009; 124: 1918-1925. https://doi.org/10.1002/ijc.24151
  17. Fukuda K, Ohta T, Oshima Y, et al., Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimers as components of drug interaction. Pharmacogenetics 1997; 7: 391-396. https://doi.org/10.1097/00008571-199710000-00008
  18. Ho PC, Saville DJ, Wanwimolruk S. Inhibition of human CYP3A4 activity by grapefruit flavonoids, furanocoumarins and related compounds. J Pharm Pharm Sci 2001; 4: 217- 227.
  19. Critchfield JW, Welsh CJ, Phang JM, et al., Modulation of adriamycin accumulation and efflux by flavonoids in HCT-15 colon cells. Activation of P-glycoprotein as a putative mechanism. Biochem Pharmacol 1994; 48: 1437-1445. https://doi.org/10.1016/0006-2952(94)90568-1
  20. Nguyen H, Zhang S, Morris ME. Effect of flavonoids on MRP1-mediated transport in Panc-1 cells. J Pharm Sci 2003; 92; 250-257. https://doi.org/10.1002/jps.10283
  21. Kimura Y, Ito H, Ohnishi R, et al., Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity. Food Chem Toxicol 2010; 48: 429-435. https://doi.org/10.1016/j.fct.2009.10.041
  22. Li X, Yun JK, Choi JS. Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos 2007; 28: 151-156. https://doi.org/10.1002/bdd.539
  23. 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
  24. 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
  25. 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
  26. 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
  27. Li X, Choi JS. Effects of quercetin on the pharmacokinetics of etoposide after oral and intravenouse administration of etoposide in rats. Anticancer Research 2009; 29: 1411-1416.
  28. Piao Y, Shin SC, Choi JS. Effects of oral kaempferol on the pharmacokinetics of tamoxifen and one of its metabolites, 4-hydroxytamoxifen, after oral administration of tamoxifen to rats. Biopharm Drug Dispos 2008; 29: 245-249. https://doi.org/10.1002/bdd.593
  29. Li X, Choi JS. Effect of genistein on the pharmacokinetics of paclitaxel administered orally or intravenously in rats. Int J Pharm 2007; 337: 188-193. https://doi.org/10.1016/j.ijpharm.2007.01.002