Experimental studies on the influence of surfactants on intestinal absorption of drugs. Cefadroxil as model drug and sodium taurocholate as natural model surfactant: studies in rat colon and in rat duodenum.

摘要

The influence of the natural bile acid surfactant sodium taurocholate (CAS 81-24-3) on colic and duodenal (i.e. the proximal third of the small intestine) absorption of cefadroxil (CAS 50370-12-2) was studied using the in situ rat gut technique, and compared with the effect of sodium lauryl sulfate (CAS 151-21-3), the most widely used synthetic anionic surfactant. Previously, the stability, compatibility, and micelle-solubilization characteristics of taurocholate were assessed in order to correct, when necessary, the absorption results. White the passive absorption rate constants (kf, h-1) determined in colon in the presence of increasing lauryl sulfate concentrations showed an asymptotic value about 7-fold higher than that of cefadroxil alone, only a 2-fold higher value was obtained in the presence of taurocholate at similar concentrations. Therefore the natural surfactant would increase the polarity of the colic absorbent membrane much less than lauryl sulfate does (about 3.5 times). The effects of taurocholate on the duodenal absorption of cefadroxil, which is the sum of a single passive process and a simultaneous carrier-mediated transport, can be summarized as follows: 1. When the working concentration of cefadroxil is far from carrier saturation (0.1 mg/ml) a slight but clear net decrease in the apparent kf value is observed in the presence of increasing concentrations of the natural surfactant (from 3.0 to 2.3 h-1) 2. When the concentration of the antibiotic in the working fluid is above carrier saturation (10 mg/ml) the picture is reversed, and a slight net increase in kf in the presence of increasing concentrations of taurocholate (from 0.8 to 1.2 h-1) is found. This means that the effect of taurocholate as a noncompetitive inhibitor of active cefadroxil transport is very much smaller than that observed with lauryl sulfate. Moreover, the increase in passive absorption relative to the synthetic surfactant is also much smaller. On the basis of allometric considerations it could be concluded that for practical purposes taurocholate does not act as a substantial absorption modifier for cefadroxil, at least in the small intestine, the main absorption site of the antibiotic. It can, however, not be considered an inert ingredient, and therefore oral administration of cefadroxil far from that of taurocholate-containing preparations, and even from lipid-rich meals should be strongly recommended.