Pretreatment with potent P-glycoprotein ligands may increase intestinal secretion in rats

The expression of P-glycoprotein is induced in cell cultures upon exposure to various inducers. Therefore, the aim of the present study was to evaluat e the in-vivo relevance of this observation, i.e, the influence of chronic pretreatments with selected drugs - all of which are ligands to P-glycoprot ein (P-gp) as demonstrated in radioligand binding studies and all of which have some or a considerable effect on P-gp expression in Caco-2 cells - on the effective intestinal permeabilities of the model compound talinolol in rats employing in-situ single-pass intestinal perfusion of three different gut segments. Talinolol was selected, because it shows high selectivity for one of the exsorptive transporters (P-gp) and its intestinal permeability is very sensitive to changes in exsorption when the perfusate concentration is low. Prior to the induction study the perfusion model was optimized reg arding the type and concentration of a competitive inhibitor which may be u sed to block the exsorption-related permeability reduction (through intesti nal exsorption) during an ongoing perfusion and would permit an intra-indiv idual comparison of the effective permeability without and with blockade of exsorption. While repetitive verapamil and talinolol dosing had no statist ically significant exsorption-inducing effect, vinblastine and rifampicin p retreatments resulted in decreased intestinal talinolol permeabilities in t he three tested gut segments, duodenum, jejunum, and colon [e.g., S-talinol ol in jejunum: control, 2.50X10(-4) cm/s; vinblastine induction, 1.48X10(-4 ) cm/s (P < 0.05); rifampicin induction, 1.51x10(-4) cm/s (P < 0.05)]. Addi tion of an efficient secretion inhibitor (vinblastine) to the perfusate per mitted the determination of the impact of inhibitable secretory processes o n the total effective permeabilities and an estimation of passive permeabil ity in the respective individual. The inhibitable permeability fractions we re higher for vinblastine than for any other pretreatment and the differenc e from control pretreatment was statistically significant for all intestina l segments (duodenum, 61.8%; jejunum, 63.1%; colon, 43,7%; S-talinolol). St atistically significant differences were also detected for rifampicin in th e perfused duodenum and jejunum (33.1 and 27.5% increase in inhibitable fra ction, respectively, for S-talinolol). These differences are explained by a significant induction of outside-directed transport in the intestinal ente rocytes by vinblastine and rifampicin. (C) 2001 Elsevier Science B.V. All r ights reserved.