TY - JOUR
T1 - Olsalazine and 6-mercaptopurine-related bone marrow suppression
T2 - A possible drug-drug interaction
AU - Lewis, Lionel D.
AU - Benin, Andrea
AU - Szumlanski, Carol L.
AU - Otterness, Diane M.
AU - Lennard, Lynne
AU - Weinshilboum, Richard M.
AU - Nierenberg, David W.
PY - 1997/10
Y1 - 1997/10
N2 - 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.
AB - 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.
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U2 - 10.1016/S0009-9236(97)90125-9
DO - 10.1016/S0009-9236(97)90125-9
M3 - Article
C2 - 9357398
AN - SCOPUS:0030657957
SN - 0009-9236
VL - 62
SP - 464
EP - 475
JO - Clinical pharmacology and therapeutics
JF - Clinical pharmacology and therapeutics
IS - 4
ER -