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Effects of trimethoprim on folate metabolism in man
Author(s) -
Kahn S. Benham,
Fein Sandra A.,
Brodsky Isadore
Publication year - 1968
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt196895550
Subject(s) - dihydrofolate reductase , leukopenia , medicine , trimethoprim , urinary system , metabolism , pharmacology , anemia , urine , physiology , biology , biochemistry , methotrexate , toxicity , antibiotics
Recent studies have demonstrated a synergistic effect of dihydrofolate reductase (DHFR) inhibitors and sulfonamides in the therapy of chronic urinary tract infections and malaria. Trimethoprim (TMP) (Ro‐56846, Hoffmann‐LaRoche) has 10,000 times more inhibitory effect on bacterial DHFR than on mammalian DHFR. Folate metabolism was evaluated in 10 normal patients treated with TMP alone for 4 weeks and 14 patients with chronic genitourinary infections treated with TMP and sulfonamides for periods up to 2 years. Parameters under study were complete blood count, bone marrow examination, serum and red blood cell folate levels, formiminoglutamic acid (FiGlu) excretion, and lobe counts of circulating neutrophiles. In order to measure folate activity a mutant strain of L. casei resistant to TMP was developed (Hitchings and Burchall, Burroughs Wellcome & Co. [U.S.A.] Inc.). In the short‐term group 1 patient developed thrombocytopenia and another anemia associated with transitional megaloblastosis, while 5 patients excreted FiGlu and all had significant elevation of lobe counts. When the drug was stopped these abnormalities disappeared in 2 weeks. One patient ingesting the combination of drugs demonstrated thrombocytopenia and leukopenia which disappeared when citrovorum factor was given despite continued administration of drugs. The dose of citrovorum factor needed to ensure hematologic normalcy was 400 µg. It is concluded that TMP has mild inhibitory effects On folate metabolism in man at the tissue level which can be overcome by administration of reduced folates.