title: Extended thiopurine metabolite assessment during 6-thioguanine therapy for immunomodulation in Crohn's disease.
abstract: 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 10(8) red blood cells) and 6-TGDP (median = 199 pmol/8 x 10(8) red blood cells). Traces of 6-TGMP (median = 39 pmol/8 x 10(8) 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/10(7)) 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.
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, the Netherlands.
authors.forename: N K H
authors.initials: NK
authors.lastname: de Boer
authors.forename: L J J
authors.initials: LJ
authors.lastname: Derijks
authors.forename: J J
authors.initials: JJ
authors.lastname: Keizer-Garritsen
authors.forename: L H J
authors.initials: LH
authors.lastname: Lambooy
authors.forename: W
authors.initials: W
authors.lastname: Ruitenbeek
authors.forename: P M
authors.initials: PM
authors.lastname: Hooymans
authors.forename: A A
authors.initials: AA
authors.lastname: van Bodegraven
authors.forename: D J
authors.initials: DJ
authors.lastname: de Jong
mesh_terms: D000328:Adult; D003424:Crohn Disease / Q000097:blood* / Q000188:drug therapy; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D013866:Thioguanine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013873:Thionucleotides / Q000097:blood*
chemical_list: D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; D013866:Thioguanine