Kinetics of metoprine, a lipid‐soluble antifolate.

Abstract

1 Using a dihydrofolate reductase inhibition assay, we have conducted eight 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 ,g/ml and an AUC of 52 /kg ml-' 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 ,ug/ml) and AUC (228 pLg ml-' 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 jig/ml) and highest AUCs (197 and 228 ,ug ml-' 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 < 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.

Drug Repurposing to Inhibit Histamine N-Methyl Transferase

“…However, their therapeutic application is limited due to their adverse effects. By clinical trials, it has been shown that metoprine produces cutaneous, gastrointestinal, and hematological toxicities which have been related to their antifolate activity [ 30 , 31 ]. In addition, metoprine binds to more than 87% of serum proteins and has a plasma half-life of 216 h [ 32 ].…”