Olsalazine and 6-mercaptopurine-related bone marrow suppression: A possible drug-drug interaction

Lionel D. Lewis, Andrea Benin, Carol L. Szumlanski, Diane M. Otterness, Lynne Lennard, Richard M. Weinshilboum, David W. Nierenberg

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Abstract

A patient with refractory Crohn's disease had two separate episodes of bone marrow suppression while receiving 50 to 75 mg 6-mercaptopurine a day and 1000 to 1750 mg olsalazine a day. This adverse reaction necessitated dose reduction of 6-mercaptopurine on the first occasion and withdrawal of 6-mercaptopurine and olsalazine on the second occasion. The patient's red blood cell thiopurine methyltransferase (TPMT) activity was 12.2 U per milliliter red blood cells (low normal rang) and her TPMT genotype was wild-type sequence for all known alleles of TPMT that result in low TPMT enzyme activity. In vitro enzyme kinetic studies confirmed the hypothesis that olsalazine and olsalazine-O-sulfate are potent noncompetitive inhibitors of recombinant human TPMT. We suggest that the patient's relatively low baseline level of TPMT activity was inhibited by olsalazine and olsalazine-O-sulfate, leading to decreased clearance of 6-mercaptopurine and its accumulation. This ultimately increased intracellular 6-thiopurine nucleotide levels to toxic concentrations, which caused bone marrow suppression.

Original languageEnglish (US)
Pages (from-to)464-475
Number of pages12
JournalClinical pharmacology and therapeutics
Volume62
Issue number4
DOIs
StatePublished - Oct 1 1997

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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