Modeling of the effect site equilibration kinetics and pharmacodynamics of racemic baclofen and its enantiomers using quantitative EEG effect measures.

The plasma to effect site equilibration kinetics and the steady-state plasma concentration-EEG effect relationship of baclofen were characterized after separate administration of racemic baclofen and its two enantiomers. Male Wistar-derived rats received an i.v. infusion of 1.25 mg of racemic, 0.63 mg of R- or 1.25 mg of S-baclofen in 10 min. Frequent arterial blood samples were obtained and the EEG was continuously quantified using aperiodic analysis. The baclofen-induced decrease in amplitudes in the 11.5 to 30 Hz frequency band was used as an EEG effect measure. The delay between plasma concentrations and EEG effect measure was best modeled by a monoexponential conductance function. No differences were observed with respect to the rate of equilibration between plasma and effect for racemic, R- and S-baclofen, with values of the time to reach 50% equilibrium (BET50ss) of (mean +/- S.E.) 23 +/- 4 min, 35 +/- 6 min and 32 +/- 7 min, respectively. The steady-state plasma concentration-EEG effect relationships of racemic and R-baclofen were characterized by the sigmoidal Emax model. The EEG effects of the S-isomer were small and best described by a linear pharmacodynamic model. The pharmacodynamic parameters of the R-isomer were: Emax = -20 +/- 2 microV/sec, EC50 = 0.61 +/- 0.11 mg/l and N = 3.7 +/- 0.7, and not significantly different from the parameters of the racemate when only the "active" R-isomer was taken into account. This indicates that no pharmacodynamic interactions between the two enantiomers occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Stereoselective transport of baclofen across the blood-brain barrier in rats as determined by the unit impulse response methodology.

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.

Absorption enhancement of rectally infused insulin by sodium tauro-24,25-dihydrofusidate (STDHF) in rats.

The bile salt derivative sodium tauro-24,25-dihydrofusidate (STDHF) has been reported to promote nasal absorption of insulin. In the present study the effect of STDHF on rectal insulin absorption was investigated in rats. At concentrations of 1 and 4% (w/v) it enhanced insulin bioavailability from 0.2 +/- 0.2 (control) to 4.2 +/- 3.2 and 6.7 +/- 2.1%, respectively, as assessed by radioimmunoassay. Insulin preparations with STDHF reduced blood glucose concentrations considerably in a concentration-dependent way. Coadministration of STDHF with Na2EDTA (0.25%, w/v) tended to increase further insulin bioavailability and hypoglycemic response. Varying the site of rectal administration did not influence these parameters.

Rectal absorption enhancement of cefoxitin and desglycinamide arginine vasopressin by sodium tauro-24,25-dihydrofusidate in conscious rats.

The effects of sodium tauro-24,25-dihydrofusidate (STDHF), an enhancer of nasal insulin absorption, on the rectal absorption of cefoxitin and desglycinamide arginine vasopressin (DGAVP) were evaluated in the rat. Cefoxitin and DGAVP proved to be poorly absorbed rectally without STDHF, but their bioavailability was considerably increased by STDHF in concentrations of 0.15 to 8% w/v. Both rectal infusion and rectal bolus delivery resulted in complete cefoxitin absorption at 4% w/v of STDHF. Delivery rate appeared to be an important factor in the effect of 4% w/v of STDHF on DGAVP bioavailability; on infusion a mean DGAVP bioavailability (+/- S.D.) of 47 +/- 12% was obtained, whereas after bolus delivery it amounted to 27 +/- 6%. For both compounds the effect of STDHF was significant at 0.5% w/v. It is concluded that STDHF is capable of actively enhancing the rectal absorption of poorly absorbed drugs, including small peptides.

Rectal absorption enhancement of des-enkephalin-gamma-endorphin (DE gamma E) by medium-chain glycerides and EDTA in conscious rats.

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.