Theoretical interpretation of extraction (in brain) of peptides including concentration variations

The transport properties of several peptides across blood-brain barrier (BBB) have been investigated theoretically in terms of simple diffusion and facilitated diffusion processes. Comparison of the calculated results from the simple diffusion and the experimental data reveals the presence of the facilitated diffusion of these substances which we have conceived of as a carrier-mediated process. The values of the partition coefficients f for these peptides were in the range 7 X 10(-4) less than or equal to f less than or equal to 200 X 10(-4). The calculated f values gave permeabilities, Ps, in lipids between 10(-7) less than or equal to Ps less than or equal to 14 X 10(-7) cm/s. These values were then used to estimate the extraction for peptides from simple diffusion alone which vary from 0.3 to 3.5% compared with the experimental extraction (0.4-12%) indicating the inadequacy of the simple diffusion alone to explain the experimental data. As for the carrier-mediated facilitated diffusion process we have used the activated-complex theory. The extraction in this case depends on the maximal rate of transport (Tmax)f and the reciprocal of the affinity constant Kt for the transport of peptides through BBB. We have deduced that (Tmax)f approximately 0.46 X 10(-3) pmol/g X s and Kt approximately 0.35 nM for Met-enkephalin (Met-ENK), Leu-enkephalin (Leu-ENK), glutathione, carnosine, alpha-MSH and MIF and (Tmax)f approximately 10 X 10(-3) pmol/g X s and Kt approximately 7 nM for AVP, beta LT, beta E and alpha E to explain the observed results. We have also obtained the quantitative variation of extraction with concentration of peptides in the brain-capillary and have established that the extraction decreases with increasing concentration of peptides, tending to a small constant value at high concentrations. It has been inferred that carrier-mediated facilitated diffusion is important for the transport of peptides across BBB.