Effects of morin on the pharmacokinetics of etoposide in 7,12-dimethylbenz[a]anthracene-induced mammary tumors in female Sprague-Dawley rats

Yang,Si  Hyung; Choi,Hyeon   Gyeom; Lim,Soo-Jeong; Lee,Myung   Gull; Kim,So  Hee

doi:10.3892/or.2012.2201

Effects of morin on the pharmacokinetics of etoposide in 7,12-dimethylbenz[a]anthracene-induced mammary tumors in female Sprague-Dawley rats

Authors:
- Si Hyung Yang
- Hyeon Gyeom Choi
- Soo-Jeong Lim
- Myung Gull Lee
- So Hee Kim
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Affiliations: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University, Gangneung, Republic of Korea, Department of Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea, College of Pharmacy, The Catholic University of Korea, Bucheon, Republic of Korea, College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon, Republic of Korea
Published online on: December 19, 2012 https://doi.org/10.3892/or.2012.2201
Pages: 1215-1223

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Abstract

Etoposide, used for the treatment of breast cancer, is mainly metabolized via hepatic cytochrome P450 (CYP) 3A4 in humans and is also a substrate for p-glycoprotein (P-gp). Morin is known to be able to modulate the activities of metabolic enzymes including CYPs and can act as a potent P-gp inhibitor. The purpose of this study was to investigate the effects of morin on the pharmacokinetics of etoposide in rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. Etoposide was administered intravenously (2 mg/kg) and orally (10 mg/kg) in control and DMBA rats without (DMBA-WOM) and with (DMBA-WM) morin (15 mg/kg). Protein and mRNA expression of CYP3A and P-gp was analyzed, and the tissue distribution of etoposide was also measured. Both protein and mRNA expression of CYP3A and P-gp was inhibited by morin in the liver, intestine and breast tumors of DMBA-WM rats. After both intravenous and oral administration of etoposide in DMBA-WM rats, the total area under the plasma concentration-time curve from time zero to infinity (AUC) of etoposide was significantly greater, and the time-averaged total body clearance (CL) of etoposide was significantly slower than those in control and DMBA-WOM rats. The amount of etoposide recovered from each tissue was significantly higher in DMBA-WM rats, especially in the breast tumor, liver and large intestine. No significant differences between control and DMBA-WOM rats were observed. Taken together, greater AUC and slower CL of etoposide in DMBA-WM rats could possibly be due to the inhibition of hepatic CYP3A (intravenous) and mainly due to the inhibition of intestinal CYP3A and P-gp (oral) by morin.

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