Effect of prokinetic agents, cisapride and metoclopramide, on the bioavailability in humans and intestinal permeability in rats of ranitidine, and intestinal charcoal transit in rats

To investigate the effect of two prokinetic drugs, cisapride and metoclopramide, on the bioavailability of drugs, a marker drug, ranitidine, was administered to healthy volunteers following pre-treatments with or without the prokinetic agents. Cisapride or metoclopramide HCl (a respective dose of 10 mg) was administered orally 30 min prior to an oral administration of ranitidine (300 mg). Serum samples were collected for a 12 h period after the administration of ranitidine and the concentration of ranitidine was determined by an HPLC method. The bioavailability parameters of the groups with the prokinetic agent pretreatment were compared with those of the control group. In addition, the effects of these prokinetic drugs on the in vitro apparent permeability of ranitidine across the rat jejunum in the Ussing chamber, and on the in vivo intestinal transit of charcoal meals in rats were also examined. The T_max of ranitidine in human subjects was shortened significantly by the either of the pretreatments (i.e., with cisapride and metoclopramide). The AUC_inf of ranitidine in human subjects was also decreased significantly in the case of cisapride pretreatment. However, no changes were observed for the values of C_max and T_1/2 by the pretreatments. Rat studies revealed that cisapride and metoclopramide had no influence on the in vitro permeability of ranitidine or the in vivo intestinal transit of charcoal meals. Therefore, these data indicated that the changes in the bioavailability parameters (i.e., T_max and AUC_inf) in humans are not related with the intestinal permeability or intestinal transit of ranitidine. The shortened T_max of ranitidine appears to be due to accelerated gastric emptying of the drug. However, underlying mechanisms for the decreased AUC_inf of ranitidine in the case of cisapride pretreatment are currently unclear.