Transport and Metabolic Pathway of Thymocartin (TP4) in Excised Bovine Nasal Mucosa

Article abstract of DOI:10.1111/j.2042-7158.1996.tb03919.x

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 amino-peptidase 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 ammopeptidases are saturated, e.g. at high TP4 concentrations.