The effect of enzyme inhibitor and absorption site following [ D ‐ala 2 , D ‐leu 5 ]enkephalin oral administration in rats

The effects of enzyme inhibitor, amastatin, and absorption site following intravenous (i.v.) oral (p.o.), jejunal and ileal administration of [ D ‐ala 2 , D ‐leu 5 ]enkephalin (YdAGFdL) were investigated in rats. Model dependent and independent pharmacokinetic parameters were obtained and compared. Linear pharmacokinetics of YdAGFdL were evaluated at 0.28 and 500 µ g doses for i.v. and at 1, 500, and 1000 µ g for p.o. and ileal routes. Plasma samples were collected and assayed for intact YdAGFdL using a radiometric thin layer chromatography. The clearance (CL) and half lives of the distribution and elimination phases following the 0.28 µ g ( n =6) i.v. dose were 42.7±26.2 (S.D.) ml/min, 0.48±0.17 min, and 3.98±0.92 min, while those of the 500 µ g dose ( n =6) were 48.0±23.3 ml/min, 0.59±0.25, and 6.81±3.12 min, respectively, suggesting apparent linear kinetics. The CL values were close to the cardiac output of rats (50 ml/min) indicating very rapid elimination from the body. Mean bioavailability ( F ) values following p.o. ( n =15), jejunal ( n =4), and ileal ( n =16) administration were 0.40±0.24% (S.E.), 1.25±0.39, and 1.78±0.40, respectively, and were not significantly different ( p <0.05) among three doses (1, 1000, 5000 µ g). The F value of YdAGFdL following ileal administration in the presence of amastatin was 8.76±4.47% ( n =6), a 22 fold increase over po administration and a five fold increase over ileal administration without an inhibitor. These results indicate that ‘effective’ oral delivery of small peptides may be achievable. Copyright © 2002 John Wiley & Sons, Ltd.