title: Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy.
abstract: Proper prospective pharmacokinetic studies of 6-mercaptopurine (6-MP) in inflammatory bowel disease (IBD) patients are lacking. As a result, conflicting recommendations have been made for metabolite monitoring in routine practice. The authors have evaluated 6-MP pharmacokinetics in IBD patients, including the genetic background for thiopurine methyltransferase (TPMT). Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine ribonucleotide (6-MMPR) concentrations were measured in 30 IBD patients at 1, 2, 4, and 8 weeks after starting 6-MP, 50 mg once daily. Outcome measures included mean 6-TGN and 6-MMPR concentrations (+/- 95% confidence interval, CI95%) and their associations with TPMT genotype, 6-MP dose, and hematologic, hepatic, pancreatic, and efficacy parameters during the 8-week period. Steady-state concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days for both 6-TGN and 6-MMPR; the concentrations were 368 (CI95% 284-452) and 2837 (CI95% 2101-3573) pmol/8 x 10 RBCs, respectively. Large interpatient variability occurred at all time points. TPMT genotype correlated with 6-TGN concentrations (0.576, P < 0.01), and patients with mutant alleles had a relative risk (RR) of 12.0 (CI95% 1.7-92.3) of developing leukopenia. A 6-MMPR/6-TGN ratio less than 11 was associated with therapeutic efficacy. Based on this pharmacokinetic analysis, therapeutic drug monitoring is essential for rational 6-MP dosing.
authors.affiliation: Department of Clinical Pharmacy, Maasland Hospital Sittard, St Laurentius Hospital, Roermond, The Netherlands. l.derijks@orbisconcern.nl
authors.forename: Luc J J
authors.initials: LJ
authors.lastname: Derijks
authors.forename: Lennard P L
authors.initials: LP
authors.lastname: Gilissen
authors.forename: Leopold G J B
authors.initials: LG
authors.lastname: Engels
authors.forename: Laurens P
authors.initials: LP
authors.lastname: Bos
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Bus
authors.forename: Joseph J H M
authors.initials: JJ
authors.lastname: Lohman
authors.forename: Wouter L
authors.initials: WL
authors.lastname: Curvers
authors.forename: Sander J H
authors.initials: SJ
authors.lastname: Van Deventer
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Hommes
authors.forename: Piet M
authors.initials: PM
authors.lastname: Hooymans
mesh_terms: D000328:Adult; D000368:Aged; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005838:Genotype; D006150:Guanine Nucleotides / Q000097:blood; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D011446:Prospective Studies; D011685:Purine Nucleotides / Q000097:blood; D013873:Thionucleotides / Q000097:blood
chemical_list: D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D011685:Purine Nucleotides; D013873:Thionucleotides; C003964:6-thioguanylic acid; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase