6 Thus, 6-TGN concentration is used as a measure of optimal efficacy (greater than 235 pmol/8 × 108 red cells) and of risk of hematological toxicity and (possibly) nodular regenerative hyperplasia of the liver (>450 pmol/8 × 108 red cells) by identifying those who are under- and overdosed. The second commonly-measured metabolite, 6-methyl

mercaptopurine (6-MMP), has been implicated in cases of hepatic toxicity (>5700 pmol/8 × 108 red cells) and therefore is used as a measure of the risk of adverse hepatic reactions.7,8 Low concentrations of both metabolites also provide evidence for poor compliance. Furthermore, the ratio of 6-MMP to 6-TGN is used to identify ‘shunters’ (ratio > 11), where there is preferential metabolism to

potentially toxic 6-MMP mTOR inhibitor away from the therapeutic 6-TGN.7 This finding has gained new significance in that allopurinol is capable of reversing this metabolic shunt, leading to therapeutic 6-TGN concentrations with efficacy in the disease and without hepatic toxicity.9 With such a story, it is difficult to see why such tests are not more readily available and utilized routinely. However, the routine use of thiopurines metabolite testing has remained controversial for three reasons. First, the quoted therapeutic range has had limited validation. It is based on retrospective analyses of clinical experience. There are methodological difficulties Torin 1 in prospectively validating the therapeutic range, including the delay between dosing and efficacy, the fluctuating course of IBD and the fact that only approximately one half of patients will respond to optimal therapy. There are reports of enhanced efficacy of azathioprine when dosage is increased in response to ‘sub-therapeutic’

6-TGN concentrations in patients not in remission, but again such studies have used retrospective data.7,10 Second, weight-based estimates of dosing in conjunction with regular tests for hematological and hepatic toxicity have been used successfully for many years. The use of surrogate markers of therapeutic dosage, such as a rise in mean corpuscular volume11 and reduced total lymphocyte count, has assisted clinicians by reassuring them that the thiopurines dose is adequate. Unfortunately, the basis for the value of such surrogate markers is limited and there Celecoxib are a number of clinical situations where such an approach might be suboptimal. For example, using this approach in a patient who is not in remission has the disadvantage of having the dose limited by the patient’s weight (no more than 1.5 mg/kg/day for 6-mercaptopurine or 3 mg/kg/day for azathioprine). Clinicians are often timid in pushing the dose of thiopurines on the basis of the patient’s weight, as retrospective and prospective studies of clinical practice have shown,12,13 and weight-based dosage correlates poorly with 6-TGN concentrations.