Abstract 5461: Effects of morin on the pharmacokinetics of etoposide in rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors

Abstract

Abstract Etoposide, used for the treatment of breast cancer, is mainly metabolized via hepatic cytochrome P450 (CYP) 3A4 in humans and rats and it has been reported that protein expression of CYP3A4 was significantly lower in breast cancer. Etoposide is also a substrate for P-glycoprotein (P-gp). Morin could modulate the activities of metabolic enzymes including CYPs and could be a potent P-gp inhibitor. The purpose of this study was to investigate the effects of morin on the pharmacokinetics of etoposide in 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor rats (DMBA rats) as an animal model of human breast cancer. Etoposide was administered intravenously (2 mg/kg) and orally (10 mg/kg) in control and DMBA rats without (DMBA-WOM) and with (DMBA-WM) oral morin (15 mg/kg). Protein and mRNA expression of CYP3A4 and P-gp were measured using immunoblot analysis and quantitative real-time PCR. After intravenous administration of etoposide in control and DMBA-WOM rats, the area under the plasma concentration-time at time zero to infinity (AUC), total body (CL) and non-renal clearance (CLNR) were comparable but in DMBA-WM rats, AUC was significantly greater (by 49.9∼64.8%), terminal half-life was significantly longer (by 54.4∼157%) and CL and CLNR were significantly slower (by 34.1∼36.1%) than those of control and DMBA-WOM rats. This suggests that DMBA did not affect considerably the hepatic metabolism of etoposide in rats. The mRNA expression of CYP3A4 was lower (by 58.4%) in DMBA rats compared to control rats but the protein expression of hepatic CYP3A subfamily in DMBA rats was comparable to control rats. The greater AUC in DMBA-WM rats could be due to slower CL and this could mainly be due to the slower CLNR than control rats, since renal clearances (CLRs) were comparable among three groups of rats. Therefore, in DMBA-WM rats, the greater AUC and slower CLNR of etoposide could be due to the inhibition of P-gp by morin. The mRNA expression of MDR1 was lower (by 30.4%) in DMBA-WM rats compared to control rats. Thus, the amount (concentration) of etoposide taken into the liver could be somewhat greater than the amount for saturation in hepatic metabolism of etoposide. After oral administration of etoposide in control and DMBA-WOM rats, AUCs were also comparable, suggesting that the effect of DMBA on the intestinal metabolism of etoposide did not seem to be considerable. However, AUC of etoposide in DMBA-WM rats was greater (by 62.5∼80.5%) than those in control and DMBA-WOM rats and this could be due to the inhibition of P-gp by morin; 34.4% lower in mRNA expression of MDR1 by morin. Taken together, the greater AUCs of etoposide in DMBA-WM rats after both intravenous and oral administration of etoposide could possibly be due to the inhibition of P-gp by morin. Supported by National Research Foundation of Korea grant R-2009-006-6765. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5461. doi:10.1158/1538-7445.AM2011-5461