title: Effects of morin on the pharmacokinetics of etoposide in 7,12-dimethylbenz[a]anthracene-induced             mammary tumors in female Sprague-Dawley rats.
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.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical                     Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Si Hyung
authors.initials: SH
authors.lastname: Yang
authors.forename: Hyeon Gyeom
authors.initials: HG
authors.lastname: Choi
authors.forename: Soo-Jeong
authors.initials: SJ
authors.lastname: Lim
authors.forename: Myung Gull
authors.initials: MG
authors.lastname: Lee
authors.forename: So Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D061605:Administration, Intravenous; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D015870:Gene Expression; D008099:Liver / Q000201:enzymology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects; D047309:Flavones
chemical_list: D015127:9,10-Dimethyl-1,2-benzanthracene; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D051544:Cytochrome P-450 CYP3A; D005047:Etoposide; D005419:Flavonoids; C008548:morin; D047309:Flavones