title: The influence of uptake from the gastrointestinal tract and first-pass effect on oral bioavailability of (Z)-alkyloxyimino penicillins.
abstract: We have investigated the contribution of uptake from the gastrointestinal 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 penicillins 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 however similar for these compounds and significantly lower than mucosal to serosal fluxes, suggesting involvement of carrier mechanisms in uptake from the mucosal surface. The order of results for the alkyloxyimino 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%). However, uptake was concentration-dependent for BRL 44154 as it was for amoxycillin, thus confirming the possible use of carrier mechanisms in absorption. These observations suggest that the poor peripheral blood concentrations of the alkyloxyimino penicillins achieved after oral dosing were not a consequence of the inability of the compounds to cross the mucosal epithelium. The biliary clearance of the alkyloxyimino penicillins was, however, considerably greater than for amoxycillin and cyclacillin, a finding which may well have been a contributory factor to the comparatively low peripheral concentrations of BRL 44154 and its analogues achieved after oral administration.
authors.affiliation: Microbial Infectivity Department, SmithKline Beecham Pharmaceuticals, Betchworth, Surrey, UK.
authors.forename: L
authors.initials: L
authors.lastname: Mizen
authors.forename: V
authors.initials: V
authors.lastname: Berry
authors.forename: G
authors.initials: G
authors.lastname: Woodnutt
mesh_terms: D000284:Administration, Oral; D000658:Amoxicillin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D003493:Cyclacillin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010406:Penicillins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D010406:Penicillins; D003493:Cyclacillin; D000658:Amoxicillin