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

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.

Morin reverses P‐glycoprotein‐mediated multidrug‐resistance in KBChR‐8‐5 cancer cell lines

“…The KBChR‐8‐5 cells have been established for the overexpression of P‐gp with continuous exposure to colchicine in a cell culture medium 35 . Morin has already been found to be both cytochrome P 450 (CYP) 3A and P‐gp inhibitor 36 . Zhang and Morris found that morin directly interacts with the P‐gp drug (substrate) binding site and inhibits P‐gp‐mediated transport function in drug‐resistant breast cancer cell lines 37 .…”

“…35 Morin has already been found to be both cytochrome P 450 (CYP) 3A and P-gp inhibitor. 36 Zhang and Morris found that morin directly interacts with the P-gp drug (substrate) binding site and inhibits P-gp-mediated transport function in drug-resistant breast cancer cell lines. 37 In this study, morin cancer cells and tissues.…”

Pegylated poly(anhydride) nanoparticles for oral delivery of docetaxel

“…However, the use of drugs that inhibit these enzymes 37 and transporters involves potential risks. In order to minimize these side effects other 38 inhibitors such as curcumin [Yan et al, 2010] or flavonoids [Yang et al, 2011] have been 39 proposed. 40 Another approach may be the use of pegylated poly(anhydride) nanoparticles.…”