Monitoring of TPMT in heart transplant recipients under immunosuppressive therapy with azathioprine.
Azathioprine (AZA) is routinely used in double and triple immunosuppressive therapy after cardiac transplantation. In some cases it causes severe myelosuppression. The interindividual differences in AZA toxicity is probably due to differences in the drug metabolism. Thiopurine methyltransferase (TPMT) is thought to be the most important enzyme in the catabolism of AZA. A deficiency in this enzyme will presumably increase the availability of 6-mercaptopurine for the anabolic pathway thereby leading to increased cytotoxicity. A 65-year-old male underwent heart transplantation at our institution with an uncomplicated course. Immunosuppression consisted of cyclosporine, prednisolone, and AZA. Several weeks after the administration of AZA, the patient developed severe leukopenia. TPMT activity was then measured in this patient and found to be below the detection limit. Subsequently the patient died from multiorgan failure due to septicaemia. As a result of this experience, we started to screen all patients for TPMT deficiency. In 58 healthy controls, the mean activity was found to be 11.8 nmol/h/ml of red blood cells (RBC) while in 13 patients on our waiting list, the mean activity was found to be 11.97 nmol/h/ml of RBC. In 15 patients after heart transplantation and azathioprine treatment, the mean activity was found to be 17.2 nmol/h/ml of RBC. We suggest screening for TPMT activity in transplant patients with leukopenia under AZA therapy. If TPMT deficiency is present, the AZA dosage should be adjusted or alternative immunosuppressive regimens should be considered.
Gummert
J F
JF
Department of Cardiothoracic and Vascular Surgery, University of Göttingen, Germany.
Schütz
E
E
Oellerich
M
M
Mohr
F W
FW
Dalichau
H
H
D000368:Aged; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D016027:Heart Transplantation / Q000009:adverse effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008780:Methyltransferases / Q000097:blood*; D015166:Monitoring, Immunologic / Q000379:methods
D015415:Biomarkers; D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine