| Abstract: | Thymocartin (TP4, Arg-Lys-Asp-Val) is the 32–35 fragment of the naturally occuring thymic factor (thymopoietin). Here studies on the nasal transport and metabolism of TP4 were performed. Freshly excised bovine nasal mucosa was taken as a model membrane. For permeation studies typical donor-receiver experiments (side-by-side) and finite-dose experiments with small volumes of highly concentrated solutions were carried out. The metabolic pathway of TP4 in nasal mucosa was found to occur according to a typical aminopeptidase cleavage pattern, stepwise forming Lys-Asp-Val and Asp-Val. TP4 metabolism experiments under reflection kinetics showed a saturation profile above 0.5 μmol mL?1. A non-linear kinetic model consisting of three steps in sequence was sufficient to describe the kinetics: for the first step saturable Michaelis-Meat kinetics, and for the second and the third step first-order kinetics were assured. The model was capable of simultaneously fitting the data for the full range of initial concentrations from 0.1 up to 1.0 μmol mL?1. Saturation kinetics was also found to be the prominent feature of the permeation experiments performed. In the lower concentration range (<0.4 μmol mL?1), transport of TP4 across nasal mucosa was controlled by metabolism, in the higher concentration range (>0.85 μmol mL?1) diffusion control became more important. We conclude that enhancement of absorption can be achieved when nasal aminopeptidases are saturated, e.g. at high TP4 concentrations. |
