Ahs/racr: The P-glycoprotein expressed in the blood-brain barrier has been associated with the restricted access of many compounds to the central nervous system. Mice lacking the /ndrla P-glycoprotein gene show an accumulation of various drugs in brain tissues. P-glycoprotein is also correlated with the phenomenon of multidrug resistance in tumour cells. To investigate the effects of drugs that modulate multidrug resistance in the selective permeability of the blood-brain barrier, mice were treated with cyclosporin A or trifluoperazine plus ivermectin, a P-glycoprotein substrate, that has a limited access to the central nervous system. When mice received an injection of cyclosporin A (50 mg/kg. intraperitoneally) or trifluoperazine (750 pg/kg, intraperitoneally) one hour prior to the administration of ivermectin (10-15 mgikg, intraperitoneally) there was an increase in the acute toxicity of ivermectin. HPLC analysis of brain tissues indicated that the ivermectin brain concentration was 2.5 times higher when mice were previously treated with cyclosporin A (50 mg/kg). These results suggest that attention should be given to the side effects of drugs that interact with P-glycoprotein and are commonly used clinically and also to the possibility of creating a pharmacological gap in the blood-brain barrier that allows the access of chemotherapeutic drugs to brain tumours.
There is evidence that the biodistribution and the pharmacokinetics of 99Tcm radiopharmaceuticals can be modified by some drugs, pathological states, irradiation and surgical procedures. Vincristine have been widely used in various chemotherapeutic protocols in oncology. We are trying to develop an animal model to assess the toxicology in different organs of compounds used as therapeutic drugs. We have studied the effect of vincristine on the distribution of 99Tcm-glucoheptonic acid (99Tcm-GHA) in female mice. After the last dose of vincristine, 99Tcm-GHA (7.4 MBq) was injected, the animals sacrificed and the percentage of radioactivity determined in the isolated organs. The percentage of activity was significantly decreased in the uterus, ovary, spleen, thymus, lymph nodes (inguinal and mesenteric), kidney and heart, but was not significantly altered in the lung, liver, pancreas, stomach, thyroid, brain and bone. Our results can be explained by the metabolic, toxic, therapeutic and immunosuppressive actions of this chemotherapeutic drug.
The many desirable characteristics of technetium-99m ((99m)Tc) have stimulated the development of labelling techniques for different molecular and cellular structures. It is generally accepted that a variety of factors can alter the biodistribution of radiopharmaceuticals and one such factor is drug therapy. Because patients on chemotherapeutic treatment receive a radiopharmaceutical in a nuclear medicine procedure, we have studied in Balb/c mice the effect of mitomycin-C on the biodistribution of the radiopharmaceutical (99m)Tc-phytic acid ((99m)Tc-PHY) used in hepatic scintigraphy. Mitomycin-C is an antineoplastic agent obtained from Streptomyces caesptosus and is used on the treatment of disseminated adenocarcinoma of the stomach or pancreas. Three doses of mitomycin-C were administered via the ocular plexus into Balb/c mice. One hour after the last dose, (99m)Tc-PHY was administered and the animals were sacrificed. The organs were isolated, the radioactivity was determined in a well counter and the percentages of radioactivity in the organs were calculated. The results have shown that the percentage radioactivity has been increased in stomach, spleen, lung, thyroid and bone, decreased in pancreas and thymus and not altered in ovary, uterus, kidney, heart, liver and brain. The changes in the distribution of (99m)Tc-PHY may be the result of metabolic processes and/or therapeutic actions produced by the administration of mitomycin-C.
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