Molecular Weight-dependent Lymphatic Transfer of Fluorescein Isothiocyanate-labeled Dextrans after Intrapulmonary Administration and Effects of Various Absorption Enhancers on the Lymphatic Transfer of Drugs in Rats

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Abstract
We have developed a new method to evaluate the transfer of macromolecular drugs to intrapulmonary lymph nodes in rats after intrapulmonary administration. By using this method, we observed that the transfer of fluorescein isothiocyanate dextrans (FDs) to the intrapulmonary lymph nodes was markedly higher than that to iliac lymph node, a non-intrapulmonary lymph node. The transfer of FDs to the intrapulmonary lymph nodes increased with increasing their molecular weights and the threshold for a high lymph node-to-plasma level ratio (CLN/CP) was between 10 and 20 kDa. The effects of absorption enhancers on the transfer of FDs to intrapulmonary lymph nodes were also examined in rats. Absorption enhancers used in this study were EDTA, sodium glycocholate (Na-GC), mixed micelles (MM), N-lauryl-β-D-maltopyranoside (LM), sodium caprate (Na-Cap). The transfer of FD-20, FD-40 and FD-70 to intrapulmonary lymph nodes after intrapulmonary administration increased in the presence of LM. In particular, the lymphatic transfer of FD-40 was remarkably increased in the presence of LM. Similarly, Na-GC and MM improved the transfer of FD-40 to intrapulmonary lymph nodes. These results suggest that absorption enhancers such as LM, Na-GC and MM are effective for improving the transfer of macromolecular drugs to intrapulmonary lymph nodes.