title: Relationship between red blood cell thiopurine methyltransferase activity and myelotoxicity in dogs receiving azathioprine.
abstract: Thiopurine methyltransferase (TPMT) produces inactive metabolites of azathioprine and, in humans, has a variable amount of activity. Humans with low TPMT activity commonly develop myelotoxicity when receiving azathioprine. Our study sought to characterize the distribution of TPMT activity in a population of dogs and to determine whether the pretreatment knowledge of red blood cell (RBC) TPMT activity could predict myelotoxicity in dogs receiving azathioprine. RBC TPMT activity was measured in 299 healthy dogs, and 9 dogs that represented a wide range of enzyme activity received azathioprine at a standard therapeutic dose for 30 days. TPMT activity in healthy dogs was log normally distributed and varied over an approximately 7-fold range. Geometric mean, minimum, and maximum RBC TPMT activities were 37.1, 16.3, and 115 nmol per gram of hemoglobin (gHb) per hour, respectively. TPMT deficiency was not identified. Two populations of TPMT activity in dogs were detected by statistical modeling (commingling analysis). Dogs with intermediate TPMT activity (14-38 nmol/gHb/h) receiving azathioprine had significantly lower neutrophil counts during week 4 than during weeks 0-3, whereas those with high activity (>39 nmol/gHb/h) did not have a significant change in neutrophil count. An analysis of TPMT activity in 6 dogs with a history of azathioprine-associated myelotoxicity in a clinical setting revealed either intermediate or high TPMT enzyme activity in all dogs, suggesting that TPMT activity, as measured in RBCs, is not the sole cause of severe azathioprine-associated myelosuppression in dogs.
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA. drod@zoomtown.com
authors.forename: Damon B
authors.initials: DB
authors.lastname: Rodriguez
authors.forename: Andrew
authors.initials: A
authors.lastname: Mackin
authors.forename: Roger
authors.initials: R
authors.lastname: Easley
authors.forename: Carolyn R
authors.initials: CR
authors.lastname: Boyle
authors.forename: Weiying
authors.initials: W
authors.lastname: Hou
authors.forename: Cory
authors.initials: C
authors.lastname: Langston
authors.forename: Amy M
authors.initials: AM
authors.lastname: Walsh
authors.forename: Michael A
authors.initials: MA
authors.lastname: Province
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
mesh_terms: D000818:Animals; D001379:Azathioprine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004285:Dogs / Q000378:metabolism*; D004912:Erythrocytes / Q000187:drug effects* / Q000201:enzymology; D005260:Female; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008780:Methyltransferases / Q000187:drug effects* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced / Q000662:veterinary; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects
chemical_list: D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine