Study On The Compatibility Mechanism Of Shichangpu And The Regulation Mechanism Of P - Glycoprotein

Aim:Herb-pair of "Angelica dahurica-Acorus tatarinowii Scholl" is widely used in clinic practice. Angelica dahurica, one of the traditional Chinese medicines in this herb-pair, has effect on expelling wind and relieving pain. The other one, Acorus tatarinowii Scholt is usually used to wake up a patient from unconsciousness and regulate the flow of Qi. The compatibility of this herb-pair is usually prescribed to treat intense excitement or ecstasy, stroke and its sequelae. P-glycoprotein (P-gp), as a drug efflux pump, has great effects on the absorption, distribution and elimination of many drugs. Xanthothoxol, Hydrate oxypeucedanin and Byakangelicin are the major active coumarins extracted from Angelicae dahuricae. Therefore, this work discussed the mechanism of the transport of Xanthotoxol, Hydrate oxypeucedanin and Byakangelicin in Angelicae Dahuricae affected by Acorus gramineus and offered a possibility for revealing the compatibility of "Angelica dahurica-Acorus tatarinowii Schott" herb-pair.Methods:This work was investigated the transport effect of the inhibitor of P-gp on the concentration-dependent, time-dependent and different parts in intestine of Xanthotoxol, Hydrate oxypeucedanin and Byakangelicin using everted the rat gut sac model, intestinal single pass perfusion and Caco-2 cell monolayer models. We further studied the synergistic effects of absorption behavior of the volatile oil of Acorus gramineus on Xanthotoxol, Hydrate oxypeucedanin and Byakangelicin.Results:1) Everted the rat gut sac model, intestinal single pass perfusion and Caco-2 cell monolayer models showed that the apparent permeability values (Papp) and absorption rate constant (Ka) of Xanthotoxol, Hydrate oxypeueedanin and Byakangelicin in intestine increased gradually with the concentration of the three drugs increased. When the concentration rises to a certain degree, the absorption increment was saturated, indicating that an active diffusion may be the dominating transport mechanism of Xanthotoxol, Hydrate oxypeucedanin and Byakangelicin. Intestinal absorption of these compounds were increased by the classic P-gp substrate Verapamil (p<0.05), which indicated that Xanthotoxol, Hydrate oxypeucedanin and Byakangelicin may be the substrates of P-gp and the transport may be mediated by P-gp; the volatile oil of Acorus gramineus enhenced the intestinal absorption of Xanthotoxol, Hydrate oxypeucedanin and Byakangelicin, this may be related to the inhibition of the intestinal P-gp activity like Verapamil (p<0.05).2) In Caco-2 cell monolayer models, the ratios of Papp BL to AP to Papp AP to BL (PDR) of Xanthotoxol, Hydrate oxypeucedanin and Byakangelicin were 1.05,1.74 and 1.54. When combined with Verapamil, the PDR of the three drugs were decreased to 0.73,0.5 and 0.43, respectively. These results suggested that the permeability of these coumarins could be affected by the P-gp inhibitors. Verapamil and volatile oil of Acorus gramineus could enhance the intestinal transportation of these coumarins, significantly.3) In intestinal single pass perfusion, jejunum is the special absorption window for Hydrate oxypeucedanin and Byakangelicin (p<0.05). But the absorption of Xanthotoxol had no significant difference between jejunum and ileum.