Dmd055228 537..540
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چکیده
Methotrexate (MTX) is the cornerstone of chemotherapy for primary central nervous system lymphoma, yet how the bloodbrain barrier (BBB) efflux transporters ABCG2 and ABCC4 influence the required high-dose therapy is unknown. To evaluate their role, we used four mouse strains, C57BL/6 (wild-type; WT), Abcg2, Abcc4, and Abcg2;Abcc4 (double knockout; DKO) to conduct brain microdialysis studies after single intravenous MTX doses of 50 mg/kg. When the area under the concentrationtime curve for plasma (AUCplasma) was used to assess systemic exposure to MTX, the rank order was Abcc4 < WT < Abcg2 < Abcg2Abcc4. Only the DKO exposure was significantly higher than that of the WT group (P < 0.01), a reflection of the role of Abcg2 in biliary excretion and Abcc4 in renal excretion. MTX brain interstitial fluid concentrations obtained by microdialysis were used to calculate the area under the concentration-time curve for the brain (AUCbrain), which found the rank order of exposure to be WT < Abcc4 < Abcg2 < Abcg2Abcc4 with the largest difference being 4-fold: 286.13 6 130 mg*min/ml (DKO) versus 66.85 6 26 (WT). Because the transporters affected the systemic disposition of MTX, particularly in the DKO group, the ratio of the AUCbrain/AUCplasma or the brain/plasma partition coefficient Kp was calculated, revealing that the DKO strain had a significantly higher value (0.236 0.09) than the WT strain (0.116 0.05). Both Abcg2 and Abcc4 limited BBB penetration of MTX; however, only when both drug efflux pumps were negated did the brain accumulation of MTX significantly increase. These findings indicate a contributory role of both ABCG2 and ABCC4 to limiting MTX distribution in
منابع مشابه
Dmd055228 537..540
Methotrexate (MTX) is the cornerstone of chemotherapy for primary central nervous system lymphoma, yet how the bloodbrain barrier (BBB) efflux transporters ABCG2 and ABCC4 influence the required high-dose therapy is unknown. To evaluate their role, we used four mouse strains, C57BL/6 (wild-type; WT), Abcg2, Abcc4, and Abcg2;Abcc4 (double knockout; DKO) to conduct brain microdialysis studies aft...
متن کاملDmd055228 537..540
Methotrexate (MTX) is the cornerstone of chemotherapy for primary central nervous system lymphoma, yet how the bloodbrain barrier (BBB) efflux transporters ABCG2 and ABCC4 influence the required high-dose therapy is unknown. To evaluate their role, we used four mouse strains, C57BL/6 (wild-type; WT), Abcg2, Abcc4, and Abcg2;Abcc4 (double knockout; DKO) to conduct brain microdialysis studies aft...
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Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, Osaka 537-0025; Osaka Prefectural Dog Management Office, Osaka 537-0025; Food Safety Promotion Division, Department of Public Health and Welfare, Osaka Prefectural Government, Osaka 540-8570; and Department of Bacterial Pathogenesis and Infection Control, National Institute of Infectious Diseases, Tokyo 208-0011, J...
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