Evidence of competitive inhibition of methotrexate absorption by leucovorin calcium in rat small intestine |
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| Institution: | 1. Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China;2. Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China;3. National Clinical Research Center for Skin and Immune Diseases, Beijing, China;4. Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany;1. Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA;2. Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA;1. Department of Endocrinology, St Vincent''s Hospital Melbourne, Melbourne, Australia;2. Department of Cardiology, St Vincent''s Hospital Melbourne, Melbourne, Australia;3. Department of Medicine, St Vincent''s Hospital Melbourne, Melbourne, Australia;4. Department of Diabetes and Endocrinology, The University of Queensland, Brisbane, Australia;5. Princess Alexandra Hospital, and School of Medicine, The University of Queensland, Brisbane, Australia;1. Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu 610041, Sichuan, China;2. Center for Advancement of Drug Research & Evaluation, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA;3. College of Physical Science and Technology, Sichuan University, Chengdu 610064, Sichuan, China;1. Research Unit, Hptal Universitario de Gran Canaria, Dr. Negrín, Multidisciplinary Organ Dysfunction Evaluation Research Network, Las Palmas de Gran Canaria, Spain;2. Research Unit, Hptal Universitario de Gran Canaria, Las Palmas de Gran Canaria, Spain;3. Morphology Department, Facultad de Veterinaria, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain;4. Animal Pathology Department, Facultad de Veterinaria, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain;5. Research Unit, Radioterapy Oncology Service, Hptal Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain;6. Microbiology Service, Hptal Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain;7. Laboratory of Microbiology, Facultad de Veterinaria, University of Las Palmas de Gran Canaria, Las Palmas, Spain |
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| Abstract: | The effect of leucovorin calcium on the intestinal absorption of methotrexate in rat small intestine was investigated using an in situ rat gut technique. First, the kinetic absorption in situ parameters for methotrexate in solution were obtained: Vm=21.54 (±2.22) μM/h; Km=10.51 (±1.08) μM; ka=0.26 (±0.03) h−1 and AIC=−188.63. The inhibitory effect of leucovorin calcium in methotrexate intestinal absorption has been investigated by perfusing of 10 μM methotrexate isotonic solutions containing increasing concentrations of leucovorin calcium (10–500 μM), and the remaining concentrations of both compounds were measured. A competitive inhibition of methotrexate absorption was detected: the apparent absorption rate constant of the drug decreased as the initial leucovorin calcium concentration increased. Higher leucovorin calcium concentrations, however, did not completely abolish the absorption of the drug (at 500 μM of leucovorin calcium, only 84% inhibition was observed). Apparent parameters characterizing the absorption of leucovorin calcium in the presence of methotrexate 10 μM were: Vmi=14.70 (±1.74) μM; Kmi=9.43 (±1.59) μM; kai=0.28 (±0.02) h−1; AIC=−191.53). We can concluded that methotrexate and leucovorin calcium compete for the same intestinal carrier system. This means that since leucovorin calcium, because of its ready conversion to other tetrahydrofolic derivatives (McEvoy, 1996. AHFS Drug Information, Bethesda, MD, pp. 751–758), is administered together with methotrexate in order to prevent the hematopoietic and reticuloendothelial toxic effects of folic acid antagonists, using high leucovorin calcium concentrations, when the urine excretion is decreased, could prevent intestinal drug reabsorption and the drug could then be excreted in the feces, thereby decreasing the risk of poisoning. |
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