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Kinetics of metoprine, a lipid‐soluble antifolate.
Author(s) -
Jones BR,
Gordon CS,
Umans J,
Reidenberg MM,
Young CW
Publication year - 1981
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.1981.tb01288.x
Subject(s) - pharmacokinetics , antifolate , dihydrofolate reductase , leukopenia , area under the curve , microgram , toxicity , pharmacology , oral administration , medicine , urine , chemistry , methotrexate , antimetabolite , biochemistry , in vitro
1 Using a dihydrofolate reductase inhibition assay, we have conducted either pharmacokinetic studies in six patients receiving metoprine. 2 The serum level v time‐curve for metoprine equivalents was irregular; first‐order elimination was not observed during the study period of 0‐ 120 h. A model‐independent analysis was therefore performed, employing the area under the curve during the first 120 h (AUC). 3 At an oral dose of 65 mg/m2 without leucovorin, a peak level of 0.6 microgram/ml and an AUC of 52 micrograms ml‐1 h produced significant leukopenia and thrombocytopenia. 4 At doses ranging from 100 mg/m2 to 175 mg/m2 orally, with leucovorin administration 40 mg/m2 intravenously at 24 and 96 h, haematologic toxicity was seen in only 1 patient who received 175 mg/m2. This patient also had the highest peak serum level (2.8 micrograms/ml) and AUC (228 micrograms ml‐1 h). 5 One partial response and one minor regression were observed in the studied patients; these two patients had the 175 mg/m2 dose, highest peak levels (2.4 and 2.8 micrograms/ml) and highest AUCs (197 and 228 micrograms ml‐1 h). The other patients had lower peak levels and AUCs and had neither therapeutic response nor hematologic toxicity. 6 The AUC and peak serum levels were linearly related to each other (P less than 0.001). 7 Total urinary excretion of dihydrofolate reductase inhibitors (as metoprine equivalents) in the first 120 h ranged from 5 to 17% of the administered dose.