| Summary: | 碩士 === 國立成功大學 === 臨床藥學與藥物科技研究所 === 101 === There have been significant advancements in the development of therapeutic proteins over past decades. It is estimated that more than 500 therapeutic proteins are presently in development, and approximately 30 therapeutic proteins currently are approved by the U.S. Food and Drug Administration (FDA). With increasing use of therapeutic proteins in poly-pharmacy settings calls for more in-depth understanding of biological interactions that can lead to toxicity or loss of pharmacological effect. However, in literature, such research is very limited. For large, polar substances such as mAbs, diffusion across vascular endothelial cells is very slow, and convection is believed to be the primary mechanism responsible for
the transport of antibody from blood fluid to interstitial fluids of tissue.
We investigated the effects of small molecule drugs, which were frequently used in the treatment of rheumatoid arthritis, on drug distribution kinetics of etanercept in a rat model. Rat were given etanercept intravenously follow by single dose of small molecule drugs intraperitoneally. After six hours, serum and skin tissue fluid concentration were measured by validated specific enzyme-linked immunoassay. Our results showed that pre-administered methylprednisolone, indomethacin and methotrexate reduce serum area under the curve (AUC) of etanercept with a shorter distribution half-life compared to control group. But in skin tissue, only methylprednisolone group has significant increase in the amount of etanercept. If we used multiple doses to maintain a high concentration of methylprednisolone, the distribution amount of etanercept would increase more.
In this study, we found co-administration of methylprednisolone and etanercept resulted in significant increase in tissue distribution of etanercept. We established a direct determination of tissue drug concentrations on rat skin to evaluate the effects of small molecule drugs on distribution kinetics of RA therapeutic proteins. This approach may also be applied in other comorbidity medications with some pharmacological interaction potentials and provide more information of drug choice
for patient under protein therapy.
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