AZATHIOPRINE METABOLISM - PHARMACOKINETICS OF 6-MERCAPTOPURINE, 6-THIOURIC ACID AND 6-THIOGUANINE NUCLEOTIDES IN RENAL-TRANSPLANT PATIENTS

Despite extensive clinical experience with azathioprine (AZA), the disposition of various AZA metabolites remains obscure. We therefore evaluated the pharmacokinetics of three AZA metabolites: 6‐mercaptopurine (6‐MP), the immediate metabolite; 6‐thiouric acid (6‐TU), the final end product; and 6‐thioguanine nucleotides (TGN), the active moiety; in eight renal transplant patients after oral administration of AZA. The low peak plasma 6‐MP level of 73.7 ± 23.7 ng/mL (mean ± SD) and the short half‐life (t1/2) of 1.9 ± 0.6 hours suggest rapid conversion of 6‐MP to other metabolites. A peak plasma 6‐TU concentration of 1210 ± 785 ng/mL was observed at 3.5 ± 0.6 hours after the AZA dose. The strong correlation between 6‐TU t1/2 and serum creatinine (r = 0.98, P = .0008) supported our previous work showing that 6‐TU is primarily excreted by the kidneys. The total TGN levels in red blood cells (RBCs) in each patient remained largely unchanged over 24 hours with the intraindividual coefficient of variation ranging from 4.4% to 29.8%. In comparison, the mean TGN level varied considerably between patients, and ranged from undetectable to 413 pmol per 8 × 108 RBCs. However, there was no apparent correlation between white cell counts on day 0 (P > .5), day 7 (P > .5), or day 14 (P > .5) and RBC TGN level. The persistence of TGN in body tissues thus provides a pharmacokinetic rationale for the conventional once or twice daily AZA regimen. Unfortunately, the long elimination t1/2 may also predispose patients to excessive accumulation of the active metabolite and gradual development of TGN‐induced myelosuppression. Further studies including more patients are required to clarify the clinical significance of the interindividual variability in RBC TGN levels. 1990 American College of Clinical Pharmacology