薬物の消化管吸収の改善，および薬物代謝に伴う脂質過酸化の研究

抄録

The absorption enhancers improve drug absorption affecting both of transcellular and paracellular routes, and the effect of the enhancers is larger in the paracellular route opening the tight junction. Theses findings are based on the effects on depolarization of fluorescence in the brush border membrane, Solomon's equation, voltage clamp method and impedance analysis of the colonic membrane. The mechanism of tight junction opening by caprate (C10) that is one of representative enhancers is revealed that C10 releses Ca ion from the intracellular store and that the released Ca ion contracts the actin filament through the activation of myosin light chain kinase. But for other representative enhancers such EDTA and palmitoyl carnitine, other different mechanism is needed but not cleared yet. Glucose transporter is found to work for the glycoside absorption, and sugar coupling with some oligo peptides enhance the absorption not only by transporter use but also by stabilization of peptides. Vitamin A protects the damage of small intestine by methotrexate and improves the absorption of nutrients.
Fluorescence spectra and protein aggregates which are produced during lipid peroxidation in the membrane such as microsome are measured directly from the membrane. They are used as indexes of the extent and site of lipid proxidation. The lipid peroxidation of heart mitochondria by doxorubicin (DXR) is demonstrated with these indexes. Chemiluminescence that is weak but measured very sensitively is also used as an index of lipid peroxidation. The chemiluminescence spectrum shows the production of the activated carbonyl and single oxygen during DXR oxidation. Naproxan which is known comparatively safe is revealed by the above indeces to give lipid peroxidation in liver during its metabolism. It is discussed that the lipid peroxidation in liver is a probable cause of liver damage which is occasionally reported for naproxen treatment.