Pharmacokinetics of azathioprine and 6‐mercaptopurine after oral administration of azathioprine

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Abstract
The pharmacokinetics of azathioprine (AZA) and its primary metabolite, 6‐mercaptopurine (6‐MP), were studied in 12 kidney transplant recipients after a single oral dose (3 mg/kg) of either azathioprine‐Pharmachemie® (AZA‐PCH) or azathioprine‐Wellcome (Imuran®, AZA‐IM), two commercially available AZA preparations, in a randomized crossover design. Plasma levels of AZA and 6‐MP were determined by high‐performance liquid chromatography (HPLC). No AZA was detected at any time after oral administration of AZA. The mean peak plasma concentration of 6‐MP (Cmax) was 144 nmol/l with a mean time to peak plasma concentration (Tmax) of 1.8 h for both AZA preparations, indicating that AZA was rapidly converted to 6‐MP. The mean plasma elimination half‐life of 6‐MP (T½) was 1.9 h after AZA‐PCH and 2.0 h after AZA‐IM. The 6‐MP levels fitted a simple first order kinetic process. At 12 h after administration, 6‐MP levels in all patients were below the detection limit. Thus, the bio‐availability of both preparations appeared to be the same. There was wide interpatient differences in 6‐MP levels. Intrapatient differences after AZA‐PCH and AZA‐IM, however, were almost negligible. One patient who was on phenobarbital and phenytoin medication had markedly lower 6‐MP levels than the other 11 patients, probably due to induction of drug‐metabolizing liver enzymes. A subsequent retrospective analysis revealed that the incidence of acute rejections was significantly higher in recipients using phenobarbital. No AZA was detected in the urine. Less than 1% of the dose of AZA was excreted in the urine as 6‐MP. There was no correlation between creatinine clearance and either urinary excretion or T½ of 6‐MP. We conclude that 1) AZA is rapidly converted to 6‐MP in vivo, 2) determination of 6‐MP plasma levels in kidney transplant recipients who receive AZA might be of clinical importance because of marked differences in 6‐MP metabolism and possible drug interactions, 3) reduction of the AZA dosage at lower creatinine clearances is disputable and may lead to undertreatment, because 6‐MP is mainly cleared by non‐renal mechanisms, 4) more frequent daily administration of AZA may be preferable because of the short half‐life of 6‐MP.