The goals of this study were to examine whether formulations, capable of releasing sulpiride (SP) in synchrony with the p-Glycoprotein (P-gp) inhibitors, verapamil (Ver) or quinidine (Qn) can increase SP relative bioavailability and to suggest a rationale approach for oral administration of SP. Jejunum of anesthetized rats was perfused with 200 or 400 microg/ml of SP either alone or together with 98 microg/ml of Ver. It was observed that while an increasing SP concentration did not cause an increase in SP blood levels, the addition of Ver or Qn to the perfusion solution caused a profound increase in SP absorption. Erodible matrix tablets, exhibiting a range of erosion rates, were prepared by manipulating the ratios of hydroxypropylmethylcellulose (HPMC) in the matrices. The tablets were designed to release the low water soluble SP and the highly water soluble Qn concomitantly over 1, 2 or 4 h. In all cases, the synchronous release increased SP bioavailability after intra-intestinal administration. The increase varied from 2.6- to 3.9-fold for the fast and the slow release formulations, respectively (compared with a control administration of a powdered mixture of SP and Qn). It is speculated that the poor oral bioavailability of SP was caused by brush border P-gp efflux. Synchronous release delivery systems of SP containing also the P-gp inhibitor Qn were able to increase SP bioavailability after intestinal administration in the rat. It is concluded that oral bioavailability of poorly absorbed drugs, in which absorption is restricted by gut wall secretory transport, may be improved by formulating them with functional adjuvants in synchronous release drug carriers.