The in vitro permeability and in vivo absorption of leuprolide in different intestinal regions were measured to investigate the feasibility for site-specific delivery of leuprolide in the gastrointestinal (GI) tract. In vitro permeability of leuprolide in the rabbit GI tract was performed using a side-by-side diffusion apparatus and the permeability coefficients in the jejunum, ileum and colon were 0.27x10(-7), 2.96x10(-7) and 7.85x10(-7)cm/s, respectively. Varying the donor drug concentrations from 2 to 10 mg/ml, the permeability coefficients were independent of the donor concentration, suggesting the transport mechanism of passive diffusion. Using an intestine loop model in anesthetized rats, bioavailabilities of leuprolide in the jejunum, ileum and colon were 1.28, 5.62 and 9.59%, respectively. Drug recovery from the loop 5 h after dosing was 10.7% in jejunum, 24.5% in ileum and 40.7% in colon. Additional in vivo studies using conscious rats showed that the bioavailability of leuprolide was less than 1% for both ileal and colonic administration. In vivo absorption of leuprolide from ileum was not significantly different from colon in conscious rats. Sodium salicylate, a permeation enhancer, was co-administered with leuprolide to the rat ascending colon, and results showed a 4-fold increase in the bioavailability in conscious rats. Thus, in vivo studies indicate that both absorption and enzymatic degradation of leuprolide in the GI tract is site-dependent and the lower intestine may be an advantageous region for oral delivery of leuprolide.