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Extended Thiopurine Metabolite Assessment During 6-Thioguanine Therapy for Immunomodulation in Crohn's Disease

From Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, the Netherlands (de Boer, van Bodegraven); Clinical Pharmacy, Maxima Medical Centre, Veldhoven, the Netherlands (Derijks); Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands (Keizer-Garritsen, Lambooy, Ruitenbeek); Clinical Pharmacy, Maasland Hospital, Sittard, the Netherlands (Hooymans); and Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands (de Jong).

The proposed metabolic advantage of 6-thioguanine (6-TG) is the direct conversion into the pharmacologically active 6-thioguaninenucleotides (6-TGN). The authors assessed metabolic characteristics of 6-TG treatment in patients with Crohn's disease (N = 7) on therapy with 20 mg 6-TG. 6-thioguanine-monophosphate (6-TGMP), 6-thioguanine-diphosphate (6-TGDP), and 6-thioguanine-triphosphate (6-TGTP) were measured by high-performance liquid chromatography analysis in erythrocytes. Thiopurine S-methyltransferase activity and total 6-TGN levels were determined by standard methods. High interindividual variance in metabolite measurements was observed. Main metabolites were 6-TGTP (median = 531 pmol/8 x 10⁸ red blood cells) and 6-TGDP (median = 199 pmol/8 x 10⁸ red blood cells). Traces of 6-TGMP (median = 39 pmol/8 x 10⁸ red blood cells) and 6-TG (2 patients) could be detected. 6-TGN levels correlated with 6-TGTP levels (r = 0.929, P = .003) and with the sum of separate nucleotides (r = 0.929, P = .003). No correlations were established between TPMT activity (median = 13 pmol/h/10⁷) and 6-TG metabolites. The 1-step metabolism of 6-TG still leads to high interindividual variance in metabolite concentrations. Total 6-TGN level monitoring may suffice for clinical practice.

Key Words: 6-Thioguanine • Crohn's disease • thiopurine • 6-thioguaninenucleotides • metabolism • TPMT • pharmacology

Address for reprints: Address for correspondence: N. K. H. de Boer, Department of Gastroenterology and Hepatology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, the Netherlands.