Influence of quercetin and chrysin on the intestinal permeability of paclitaxel, a substrate of P-glycoprotein and CYP3A4 using in vitro rat gut sac

P-glycoprotein (p-gp) and cytochrome p450 3a4 (cyp3a4) play a significant role in the disposition and elimination of drugs. the objective of this study was to investigate the mechanism underlying the interaction between paclitaxel (substrate of p-gp and cyp3a4), quercetin and chrysin using everted gut sacs in vitro models. non-everted gut sacs (negs) were used to evaluate the transport of paclitaxel from mucosal to serosal (m-to-s) side of the intestine. negs were loaded with 1 ml of modified krebs-ringer bicarbonate (krb) buffer containing paclitaxel (50μg/ml) in the presence or absence of known p-gp and cyp3a4 inhibitors. each sac was placed in individual 50 ml erlenmeyer flasks containing 30 ml of oxygenated (o2/co2; 95:5) krb and incubated at 37 ºc for 60 min in a shaker bath. aliquots (150 μl) of serosal fluid were collected at 10, 20, 30, 40, 50, 60, 70, 80 and 90 min and then replaced by the same volume of buffer. the paclitaxel levels in incubated samples were determined by uv-spectrophotometer at 227 nm. the same experiment was repeated with everted gut sacs (egs) to study the transport of paclitaxel from serosal to mucosal (s-to-m) side of the intestine. in vitro study results showed that the apparent permeability coefficient (papp), net efflux and efflux ratio of paclitaxel were significantly increased by quercetin and chrysin. the present study revealed that quercetin and chrysin enhanced the intestinal absorption of paclitaxel by inhibiting its absorption via p-gp and/or the cyp3a4-mediated biotransformation in intestine.