Effects Of Two Excipients To The Disposition Of Rifampicin And Diazepam Based On P-glycoprotein

The aim of this study was to investigate the effects of Pluronic(?) F68 and Labrasol on the intestinal absorption and pharmacokinetics of rifampicin in rats, and examine the effects of Pluronic(?) F68 on the plasma and brain concentration of diazepam in mice.Methods1. Wistar rats were divided into eight groups. A bolus dose of perfusion buffer containing rifampicin, with or without Pluronic(?) F68 (3%,0.1%,0.05%), Labrasol (3%,0.1%,0.05%) or verapamil, was allowed to perfuse with intestinal segment by rat single pass intestinal perfusion technique. Thereafter, the drug absorption rate constant (Ka) and the effective intestinal permeability (Peff) were calculated.2. Wistar rats were divided into four groups. After a polyethylene tube was inserted into the right fermoral artery, the rats were received rifampicin orally alone or in combination with Labrasol, Pluronic(?) F68, verapamil, respectively. Blood samples were withdrawn at different time points. After the plasma samples were pretreated, they were directly determined by HPLC, and the concentration-time curves were obtained. The main pharmacokinetic parameters including AUC0-t, t1/2, Cl, Cmax, Ke for rifampicin were calculated using DAS 2.0.3. Thirty kunming mice were divided into five groups. The mice were received diazepam orally alone or in combination with Pluronic(?) F68 (600,400,250 mg/kg), respectively. Then the blood and brain samples were withdrawn at 40 min after oral administration and the biological samples were determined by HPLC.ResultsI. Verapamil and excipients (0.05%,0.1%) significantly increased the intestine absorption of rifampicin (P<0.05). Labrasol or Pluronic(?) F68 (0.1%), co-perfused with rifampicin, increased in situ permeability by 2.7-fold and 2.5-fold, respectively. Similarly,0.05% excipients also increased in situ permeability, but to a small extent (P>0.05).2. The excipients Pluronic(?) F68/Labrasol/verapamil could change the pharmacokinetic parameters of rifampicin significantly. The t1/2 of rifampicin was prolonged by 38%,25% and 35% (P<0.05). The clearance of rifampicin in the group was 0.457 L/h/kg, but was reduced to 0.265, 0.280 and 0.244 L/h/kg with Pluronic(?) F68, Labrasol and verapamil, respectively (P<0.05). In addition, verapamil treatments increased the AUC0-t significantly in comparison to rifampicin group (P<0.05), and Labrasol and Pluronic(?) F68 increased the AUC0-t by 2.7-fold and 2.5-fold, respectively. Moreover, there was no significant increase between verapamil and rifampicin group (P>0.05).3. The drug concentrations in mice plasma and brain of verapamil group were improved 1.83-fold and 2.20-fold in camparison to rifampicin group (P<0.01), and Pluronic(?) F68 at high concentration increased them by 1.61-fold and 1.56-fold, respectively (P<0.05). In addition, the plasma concentration of diazepam in mice was also improved 1.60-fold in the presence of Pluronic(?) F68 at middle concentration (P<0.05), and there was no significant increase in brain (P >0.05). On the other hand, the plasma and brain concentration of Pluronic(?) F68 at middle or high concentration was not affected significantly in camparison to verapamil group (P>0.05).ConclusionThe excipients, possessing P-gp inhibitory activity, could increase the intestinal absorption and change the pharmacokinetic parameters of rifampicin in rats. In addition, Pluronic(?) F68 and Labrasol could increase the plasma and brain concentration of diazepam in mice. Consequently, attention should be exercised to the effects of excipients on P-gp function during the development of formulations, and modulated the disposition of drug preferably.