Olsalazine and 6-mercaptopurine-related bone marrow suppression: a possible drug-drug interaction.
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 1.2 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.
Lewis
L D
LD
Department of Medicine, Dartmouth Medical School, Hanover, NH, USA.
Benin
A
A
Szumlanski
C L
CL
Otterness
D M
DM
Lennard
L
L
Weinshilboum
R M
RM
Nierenberg
D W
DW
D000293:Adolescent; D000636:Aminosalicylic Acids / Q000009:adverse effects* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects*; D003424:Crohn Disease / Q000188:drug therapy / Q000276:immunology*; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015122:Mercaptopurine / Q000009:adverse effects* / Q000627:therapeutic use; D011241:Prednisone / Q000009:adverse effects* / Q000627:therapeutic use
D000636:Aminosalicylic Acids; D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; C032587:olsalazine; D011241:Prednisone