Mizen L, Berry V, Woodnutt G
Microbial Infectivity Department, SmithKline Beecham Pharmaceuticals, Betchworth, Surrey, UK.
J Pharm Pharmacol. 1995 Sep;47(9):725-30. doi: 10.1111/j.2042-7158.1995.tb06731.x.
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.
我们已经研究了胃肠道摄取及首过效应对一系列（Z）-烷氧基亚氨基青霉素在小鼠体内口服生物利用度低的影响。肠道囊和灌注小肠的研究表明，这些青霉素能够穿过黏膜上皮，尽管程度低于阿莫西林和环青霉素，后两者在人和动物体内均具有优异的口服生物利用度。在空肠肠道囊中，BRL 44154的黏膜到浆膜通量约为阿莫西林的一半，比环青霉素少四倍，并且对所有药物而言，摄取均依赖于pH值。然而，这些化合物的浆膜到黏膜通量相似，且显著低于黏膜到浆膜通量，这表明载体机制参与了从黏膜表面的摄取过程。烷氧基亚氨基青霉素的结果顺序与在小鼠中观察到的口服生物利用度顺序一致。对于烷氧基亚氨基青霉素，从灌注肠道中的摄取量在5.5%至9.9%之间，这些值显著低于阿莫西林（13.2%）和环青霉素（33.3%）。然而，BRL 44154的摄取与阿莫西林一样依赖于浓度，从而证实了吸收过程中可能存在载体机制。这些观察结果表明，口服给药后烷氧基亚氨基青霉素外周血浓度低并非由于化合物无法穿过黏膜上皮。然而，烷氧基亚氨基青霉素的胆汁清除率远高于阿莫西林和环青霉素，这一发现很可能是口服给药后BRL 44154及其类似物外周浓度相对较低的一个促成因素。
