engleski

Acute kidney injury, agranulocytosis, drug-induced liver injury, and posterior reversible encephalopathy syndrome caused by high- dose methotrexate-possible role of low activity ABC and SLC drug transporters

Here, we present a 26-year-old male with B cell ALL who after the second infusion of HD-MTX (5000 mg/m2 IV) and extremely high MTX serum concentration (142.56 μmol/L) suffered damage to four organ systems. We elaborated that it could have been due to combination of genetic predisposition and pharmacokinetic interactions between MTX and concomitant drugs (pantoprazole, ketoprofen, ciprofloxacin, and later with piperacillin/tazobactam. Slow MTX elimination ensued during the next 16 days. Subsequently, the patient developed AKI (with a fall of estimated glomerular filtration rate to 45 mL/min/1.73 m2), severe neutropenia, and a rise in alanine aminotransferase (234 U/L) followed by encephalopathy syndrome. The patient was found to be homozygous for SLCO1B1 T521C, ABCB1 G2677T/A, C3435T, C1236T, ABCC2 G1249A, low activity transporters alleles and heterozygous for MTHFR C677T and A1298C. A strong genetic predisposition to prolonged MTX elimination in combination with clinically significant pharmacokinetic interactions could explains extremely elevated MTX concentration, prolonged elimination and adverse MTX side effects.

methotrexate ; drug transporters ; drug side effects ; genetic polymorphism ; drug- drug interactions

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