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

Abstract

The intestinal permeability of hexarelin and EP 51389, two growth hormone releasing 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 the basolateral-to-apical (BL-to-AP) direction using excised rat jejunal segments. The effect of EP 51389 on P-glycoprotein (P-gp) was evaluated by rhodamine 123 accumulation on monolayers of CH RC5 cells with increasing concentrations of EP 51389. Hexarelin and EP 51389 permeability were found to be < 1%. Permeability coefficients (P app) were 18.87 ± 2.86 (×10 −7 cm/s) and 5.87 ± 0.45 (×10 −7 cm/s) for hexarelin and EP 51389, respectively. Bidirectional studies revealed that hexarelin transport was similar in both directions. EDTA did not influence hexarelin permeability. Permeability was predominantly secretory for EP 51389 as P app in the BL-to-AP direction [32.56 ± 6.11 (×10 −7 cm/s)] was greater than AP-to-BL. Confirming involvement of a secretory transport system, chlorpromazine inhibited EP 51389 transport across the jejunum. EP 51389 inhibited P-gp in a dose dependent manner resulting in the intracellular accumulation of rhodamine in CH RC5 cells. These results suggest that: 1) the intestinal permeability 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.