Permeability of the peptidic GH secretagogues hexarelin and EP 51389, across rat jejunum

The intestinal permeability of hexarelin and EP 51389, two growth hormone r eleasing hexa- and tri- peptide analogues, was assessed in vitro with side- by-side diffusion chambers in the apical-to-basolateral (AP-to-BL) and in t he basolateral-to-apical (BL-to-AP) direction using excised rat jejunal seg ments. The effect of]EP 51389 on P-glycoprotein (P-gp) was evaluated by rho damine 123 accumulation on monolayers of CH(R)C5 cells with increasing conc entrations of EP 51389. Hexalelin and EP 51389 permeability were found to b e < 1%. Permeability coefficients (P-app) were 18.87 <plus/minus> 2.86(x 10 (-7) cm/s) and 5.87 +/- 0.45 (x 10(-7) cm/s) for hexarelin and EP 51389, re spectively, Bidirectional studies revealed that hexarelin transport was sim ilar in both directions. EDTA did not influence hexarelin permeability, Per meability was predominantly secretory for EP 51389 as P-app in the BL-to-AP direction [32.56 +/- 6.11 (x 10(-7) cm/s)] was greater than AP-to-BL. Conf irming involvement of a secretory transport system, chlorpromazine inhibite d EP 51389 transport across the jejunum, EP 51389 inhibited P-gp in a dose dependent manner resulting in the intracellular accumulation of rhodamine i n CH(R)C5 cells. These results: suggest that: 1) the intestinal permeabilit y of hexarelin and EP 51389 is poor; 2) the passage of hexarelin is mainly via a transcellular passive pathway since the contribution of paracellular permeability to the overall permeability is rather low; 3) P-gp may act as a potential barrier for the intestinal absorption of EP 51389. (C) 2001 Els evier Science Inc. All rights reserved.