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Olsalazine and 6‐mercaptopurine‐related bone marrow suppression: A possible drug‐drug interaction
Author(s) -
Lewis Lionel D.,
Benin Andrea,
Szumlanski Carol L.,
Otterness Diane M.,
Lennard Lynne,
Weinshilboum Richard M.,
Nierenberg David W.
Publication year - 1997
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(97)90125-9
Subject(s) - thiopurine methyltransferase , mercaptopurine , bone marrow suppression , pharmacology , bone marrow , drug , medicine , drug interaction , chemistry , azathioprine , chemotherapy , disease
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 range) 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. Clinical Pharmacology & Therapeutics (1997) 62 , 464–475; doi: