Effects of Morin on the Pharmacokinetics of Docetaxel in Rats with 7,12-Dimethylbenz[a]anthracene (DMBA)-induced Mammary Tumors

다국어 초록 (Multilingual Abstract)

Docetaxel is a P-glycoprotein (P-gp) substrate and metabolized via cytochrome P450 (CYP) 3A subfamily in rats. Morin is an inhibitor of both CYPs and P-gp. Hence, the effects of morin on the intravenous and oral pharmacokinetics of docetaxel were investigated using 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor rats (DMBA rats) as an animal model of human breast cancer. Docetaxel was administered intravenously (4 mg/kg) and orally (20 mg/kg) without and with morin (15 mg/kg) in DMBA rats. After the intravenous administration of docetaxel in control and DMBA rats with and without morin, the values of non-renal clearance and area under the plasma concentration-time (AUC) for docetaxel were comparable. Morin did not increase AUC or the absolute oral bioavailability (F) for docetaxel after the oral administration of docetaxel in control and DMBA rats with and without morin. The inhibition of hepatic and intestinal metabolism of docetaxel by morin and/or DMBA and the effect of intestinal P-gp inhibition by morin on the pharmacokinetics of docetaxel did not seem to be considerable in DMBA-induced mammary tumor rats.

참고문헌 (Reference)

1 Sandström, M., "The pharmacokinetics of epirubicin and docetaxel in combination in rats" 44 : 469-474, 1999

2 Baker, S. D., "Simultaneous analysis of docetaxel and the formulation vehicle polysorbate 80 in human plasma by liquid chromatography/tandem mass spectrometry" 324 : 276-284, 2004

3 Fendl, K. C., "Role of tamoxifen in the induction of hormone-independent rat mammary tumors" 52 : 235-237, 1992

4 Sparreboom, A., "Preclinical pharmacokinetics of paclitaxel and docetaxel" 9 : 1-17, 1998

5 Pathak, S. M., "Pre-clinical evidence of enhanced oral bioavailability of the P-glycoprotein substrate talinolol in combination with morin" 31 : 202-214, 2010

6 Davies, B., "Physiological parameters in laboratory animals and humans" 10 : 1093-1095, 1993

7 Bruno, R., "Pharmacokinetics and metabolism of Taxotere (docetaxel)" 17 : 305-313, 1993

8 Gibaldi, M., "Pharmacokinetics" Marcel-Dekker 1982

9 Yang, S. H., "Pharmacokinetic interaction between tamoxifen and ondansetron in rats: non-competitive (hepatic) and competitive (intestinal) inhibition of tamoxifen metabolism by ondansetron via CYP2D subfamily and 3A1/2" SPRINGER 65 (65): 407-418, 2010

10 Huggins, C., "Mammary cancer induced by a single feeding of polymucular hydrocarbons, and its suppression" 189 : 204-207, 1961

11 Marre, F., "Hepatic biotransformation of docetaxel (Taxotere) in vitro: involvement of the CYP3A subfamily in humans" 56 : 1296-1302, 1996

12 Thummel, K. E., "Gut instincts: CYP3A4 and intestinal drug metabolism" 117 : 3173-3176, 2007

13 Hodek, P., "Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450" 139 : 1-21, 2002

14 Zhang, S., "Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein- mediated transport" 304 : 1258-1267, 2003

15 Choi, Y. H., "Effects of tesmilifene, a substrate of CYP3A and an inhibitor of P-glycoprotein, on the pharmacokinetics of intravenous and oral docetaxel in rats" Pharmaceutical Press 62 (62): 1084-1088, 2010

16 Piao, Y. J., "Effects of morin on the pharmacokinetics of nicardipine after oral and intravenous administration of nicardipine in rats" 60 : 625-629, 2008

17 Li, X., "Effects of morin on the pharmacokinetics of etoposide in rats" 28 : 151-156, 2007

18 Shin, S. C., "Effects of morin on the bioavailability of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats" INT INST ANTICANCER RESEARCH 22 (22): 391-395, 2008

19 Jun Shik CHOI, "Effects of Quercetin on the Bioavailability of Doxorubicin in Rats: Role of CYP3A4 and P-gp Inhibition by Quercetin" 대한약학회 34 (34): 607-613, 2011

20 Hyun Jin Choi, "Effects of Morin Pretreatment on the Pharmacokinetics of Diltiazem and Its Major Metabolite, Desacetyldiltiazem in Rats" 대한약학회 28 (28): 970-976, 2005

21 Lwin, Z., "Economic evaluation of docetaxel for breast cancer" 10 : 283-290, 2009

22 Vaclavikova, R., "Different in vitro metabolism of paclitaxel and docetaxel in humans, rats, pigs, and minipigs" 32 : 666-674, 2004

23 Suh, J. H., "Cysteine effects on the pharmacokinetics of etoposide in protein-calorie malnutrition rats: increased gastrointestinal absorption by cysteine" INFORMA HEALTHCARE 41 (41): 885-894, 2011

24 Chiou, W. L., "Critical evaluation of the potential error in pharmacokinetic studies using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve" 6 : 539-546, 1978

25 Malingré, M. M., "Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel" 19 : 1160-1166, 2001

26 Ben Reguiga, M., "Bioavailability and tissue distribution of docetaxel, a Pglycoprotein substrate, are modified by interferon-alpha in rats" 59 : 401-408, 2007

27 Russo, J., "Atlas and histologic classification of tumors of the rat mammary gland" 5 : 187-200, 2000

28 Choi, B. C., "Altered pharmacokinetics of paclitaxel by the concomitant use of morin in rats" 323 : 81-85, 2006