INTESTINAL-ABSORPTION OF DRUGS .4. THE INFLUENCE OF TAUROCHOLATE AND L-CYSTEINE ON THE BARRIER FUNCTION OF MUCUS

The results in this report show that taurocholate (TC) is able to alter the rheological properties ('viscosity') of native porcine mucus in vitro. Below the critical micelle concentration (CMC) the viscosity reduction is dependent on the concentration of TC; above the CMC the viscosity of the mucus is not decreased further: this indicates that the effect of TC on the viscosity of the mucus is not the result of micellar solubilization. The effect of TC on the intralurninal release of mucus components (hexoses) in the small intestine of the rat, is also concentration-dependent: below the CMC (about 8 mM) the hexose output is not altered, but above the CMC the hexose output is increased to a concentration-independent level. The mucolytic agent l-cysteine also reduces the viscosity of mucus in vitro and induces an increase in the hexose output in vivo. Absorption experiments with 10 mM TC in an isolated segment of the small intestine of the rat reveal that the disappearance rate of dantrolene (DA) and ketoconazole (KE) is reduced by TC, but apparently this reduction is almost proportional to the decrease in the fraction of the drug free in solution due to micellar solubilization. DA and KE are not solubilized by l-cysteine and absorption experiments with l-cysteine reveal that the absorption rate of these drugs is not affected by l-cysteine. These results indicate that TC and L-cysteine do not have a measurable or pronounced effect on the absorption barrier in vivo. An explanation for these results may be that, if the rate-limiting barrier to the transport of lipophilic drugs from the lumen to the serosa is located in the mucous layer, then the effects on the mucus by TC and L-cysteine must be neutralized by a compensatory mechanism, which is restoring the barrier function instantaneously, e.g. by the secretion of mucus from the goblet cells. © 1990.