Guillaume et al1 may have failed to identify a therapeutic response in their azathioprine-treated bullous pemphigoid patients by omitting to take account of interindividual differences in azathioprine metabolism. Following an oral dose, azathioprine is rapidly converted to 6-mercaptopurine that, in turn, undergoes extensive metabolism along three competing routes (Figure). In vivo methylation is a major catabolic route catalyzed by the enzyme thiopurine methyltransferase (TPMT). There is wide patient variability in TPMT activity that is controlled by a common genetic polymorphism.2 Eighty-nine percent of the population have high, and 11% intermediate, enzyme activities while one in 300 subjects has very low or absent TPMT activity. Subjects with low TPMT activity produce increased quantities of the active nucleotide metabolites of azathioprine and are more vulnerable to the toxic effects of this drug.3 Conversely, patients with high TPMT activity metabolize azathioprine more rapidly via this route and may fail to
Anstey A. Controlled Trial of Azathioprine and Plasma Exchange in Addition to Prednisolone in the Treatment of Bullous Pemphigoid. Arch Dermatol. 1993;129(9):1203–1204. doi:10.1001/archderm.1993.01680300133025
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