Transport and metabolic pathway of thymocartin (TP4) in excised bovine nasal mucosa.
Thymocartin (TP4, Arg-Lys-Asp-Val) is the 32-35 fragment of the naturally occurring 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 mumol 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 mumol mL-1. Saturation kinetics was also found to be the prominent feature of the permeation experiments performed. In the lower concentration range (< 0.4 mumol mL-1), transport of TP4 across nasal mucosa was controlled by metabolism, in the higher concentration range (> 0.85 mumol 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.
Lang
S
S
Department of Pharmacy, Swiss Federal Institute of Technology Zurich (ETH), Switzerland.
Langguth
P
P
Oschmann
R
R
Traving
B
B
Merkle
H P
HP
D000042:Absorption; D000276:Adjuvants, Immunologic / Q000378:metabolism*; D000281:Administration, Intranasal; D000818:Animals; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D007700:Kinetics; D008954:Models, Biological; D009297:Nasal Mucosa / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism* / Q000502:physiology; D010539:Permeability; D013946:Thymopoietins / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D010446:Peptide Fragments; D013946:Thymopoietins; C045802:thymocartin