The blood-brain barrier transport characteristics of racemic baclofen and the separate R- and S-enantiomers have been determined in vivo in rats by using the unit impulse response methodology. Transport rate was determined as blood-brain barrier clearance, the volume of plasma per unit time cleared of baclofen by transport across the blood-brain barrier. Plasma elimination kinetics and CSF elimination kinetics did not differ among racemic baclofen and the R- and S-enantiomers. Transport of each compound could be described by a linear V(t) curve, suggesting the absence of saturable transport processes in the concentration range studied. However, for R-baclofen the blood-brain barrier clearance (4.7 +/- 1.0 microliters/min, mean +/- SE; n = 6) and cumulative transported amount (0.085 +/- 0.007%; n = 6) were significantly higher than these values for the S-enantiomer (1.1 +/- 0.3 microliters/min, 0.031 +/- 0.005%; n = 6) and racemic baclofen (1.0 +/- 0.1 microliters/min, 0.036 +/- 0.003%; n = 6). These findings indicate that there is stereoselective transport of baclofen across the blood-brain barrier.

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The stability of the neuroleptic peptide des-enkephalin-gamma-endorphin (DE gamma E; Org 5878) in the rectal lumen and the rectal bioavailability of DE gamma E were investigated in conscious rats. Furthermore, the influence of peptidase inhibition, peptidase saturation, and absorption enhancement on DE gamma E bioavailability were evaluated. Na2EDTA (0.25%, w/v) prolonged the degradation half-life of DE gamma E in the ligated colon from 33 +/- 7 to 93 +/- 45 min. Without adjuvant, tritium-labeled DE gamma E was absorbed from the rat rectum to a very low extent (0-4%). After administration of an excess of unlabeled DE gamma E or with Na2EDTA, comparable results were obtained. The medium-chain glyceride preparation MGK markedly enhanced the rectal DE gamma E bioavailability, up to 8-20%, which was further increased to 10-44% by coadministration of Na2EDTA. No substantial influence of varying the rectal delivery rate was observed. The results suggest that absorption enhancement and enzyme inhibition both are essential for effective increase of rectal peptide bioavailability.