Determining Intestinal Metabolism and Permeability for Several Compounds in Rats. Implications on Regional Bioavailability in Humans

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Abstract
Purpose. To investigate the regional differences in small intestinal (SI) metabolism and permeability for several compounds and to ascertain the potential significance of these differences on the reported reductions in regional bioavailability in humans. Methods. The regional SI metabolism and permeability of captopril, didanosine (ddl), mannitol, ofloxacin and zidovudine (ZDV) were investigated in rats using a Single Pass Intestinal Perfusion (SPIP) procedure or intestinal homogenates. Results. ddI was metabolized to a greater extent in the upper SI whereas captopril was metabolized to a greater extent in the lower SI. Relatively low homogenate concentrations resulted in significant degradation of captopril in the upper and lower SI. All other compounds were stable and changes in the buffer system or the initial concentration did not affect the results. The SI permeabilities of all compounds, with the exception of mannitol, decreased linearly with respect to SI location and the slopes of the corresponding normalized regression lines were not significantly different. Conclusions. It has been reported that captopril and ddl demonstrate regional intestinal bioavailability in several species including humans. The current results suggest that the reported reduction in the lower SI bioavailability of captopril may be a result of a reduction in permeability and an increase in intestinal metabolism whereas for ddl, the reduction in the lower SI bioavailability appears to be attributable to a reduction in intestinal permeability. Other factors such as luminal metabolism may also significantly effect regional differences in the intestinal bioavailability of ddl or captopril. Based on these results, a strong possibility exists that ofloxacin and ZDV may also demonstrate regional differences in intestinal bioavailability.