A pharmacogenetic basis for the safe and effective use of azathioprine and other thiopurine drugs in dermatologic patients

Abstract

The safe and effective use of cytotoxic drugs for debilitating and sometimes life-threatening dermatoses is of great interest. The thiopurine antimetabolite group of drugs that includes azathioprine, as well as 6-mercaptopurine and 6-thioguanine, have been widely used as immunosuppressant and steroid-sparing agents in a variety of cutaneous diseases. Numerous recent review articles have highlighted the potential for serious immunosuppression with these agents. l-6 However, there is a significant lack of information in the dermatologic literature concerning the important pharmacogenetic variations in thiopurine metabolism responsible for some cases of myelosuppression. During the past 15 years the genetic basis of variation in the activity of a key enzyme in thiopurine metabolism, thiopurine methyltransferase (TPMT), and its role in myelosuppression have been evaluated.7-10 Mounting evidence suggests that measurement of TPMT activity provides a rational basis for identifying enzyme-deficient patients at risk for profound myelosuppression, partially enzyme-deficient patients potentially at risk for myelosuppression, and perhaps even those with high enzyme activities who may be classified as therapeutic failures because of inadequate standard, empiric dosing with azathioprine and other thiopurine drugs. TPMT activity can be determined in peripheral red blood cell lysates, and this activity correlates with enzyme activity in the major drug metabolizing organ, the liver. 11’ l2 The clinical importance and utility of this