Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia.
Because trimethoprim-sulfamethoxazole (TMP-SMX) causes neutropenia in children with leukemia, we investigated the possibility that pharmacokinetic interaction between methotrexate (MTX) and TMP-SMX causes accumulation of the antileukemia agent. We studied the pharmacokinetics of MTX given intravenously or orally to nine children with acute lymphoblastic leukemia, once with and once without TMP-SMX. There was an increase in free MTX fraction during TMP-SMX therapy in all patients, from (mean +/- SD) 37.4 +/- 11% without TMP-SMX to 52.2 +/- 6.4% with TMP-SMX (p less than 0.01). Plasma clearance of total MTX did not change significantly, whereas clearance of free MTX decreased significantly (from 12.5 +/- 4 to 7.6 +/- 1.5 ml/kg/min; p less than 0.05). There was a consistent decrease in the renal clearance of free MTX (from 12.1 +/- 6.8 to 5.6 +/- 2.4 ml/kg/min; p less than 0.05). Elimination half-life of MTX was not affected significantly by TMP-SMX. There was a significant correlation between serum concentrations of TMP-SMX and the percentage of decrease in the renal clearance of free MTX (r = 0.91; p less than 0.05). These changes in protein binding and tubular clearance of MTX, caused by competition with TMP-SMX, result in a mean 66% increase in systemic exposure to MTX and may explain the myelotoxicity often observed with the coadministration of the two drugs.
Ferrazzini
G
G
Division of Clinical Pharmacology, Hospital for Sick Children, Toronto, Ontario, Canada.
Klein
J
J
Sulh
H
H
Chung
D
D
Griesbrecht
E
E
Koren
G
G
D001853:Bone Marrow / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011485:Protein Binding; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D008727:Methotrexate