THE INFLUENCE OF UPTAKE FROM THE GASTROINTESTINAL-TRACT AND FIRST-PASS EFFECT ON ORAL BIOAVAILABILITY OF (Z)-ALKYLOXYIMINO PENICILLINS

We have investigated the contribution of uptake from the gastrointesti nal tract and first-pass effect to the poor oral bioavailability of a series of (Z)-alkyloxyimino penicillins in mice. Investigative studies in gut sacs and perfused small intestine demonstrated that these peni cillins were able to pass across the mucosal epithelium although to a lesser extent than amoxycillin and cyclacillin, both of which exhibit excellent oral bioavailability in man and animals. In the jejunal gut sacs the mucosal to serosal flux for BRL 44154 was approximately half that of amoxycillin and four times less than that of cyclacillin, and for all, uptake was pH dependent. The serosal to mucosal fluxes were h owever similar for these compounds and significantly lower than mucosa l to serosal fluxes, suggesting involvement of carrier mechanisms in u ptake from the mucosal surface. The order of results for the alkyloxyi mino penicillins paralleled that observed for oral bioavailability in the mouse. For the alkyloxyimino penicillins, between 5.5 and 9.9% was taken up from the perfused intestine, values which were significantly less than those for amoxycillin (13.2%) and cyclacillin (33.3%). Howe ver, uptake was concentration-dependent for BRL 44154 as it was for am oxycillin, thus confirming the possible use of carrier mechanisms in a bsorption. These observations suggest that the poor peripheral blood c oncentrations of the alkyloxyimino penicillins achieved after oral dos ing were not a consequence of the inability of the compounds to cross the mucosal epithelium. The biliary clearance of the alkyloxyimino pen icillins was, however, considerably greater than for amoxycillin and c yclacillin, a finding which may well have been a contributory factor t o the comparatively low peripheral concentrations of BRL 44154 and its analogues achieved after oral administration.