PMID- 23932783 OWN - NLM STAT- MEDLINE DCOM- 20141017 LR - 20231213 IS - 1876-4479 (Electronic) IS - 1873-9946 (Linking) VI - 8 IP - 2 DP - 2014 Feb TI - The pharmacokinetic effect of adalimumab on thiopurine metabolism in Crohn's disease patients. PG - 120-8 LID - S1873-9946(13)00242-0 [pii] LID - 10.1016/j.crohns.2013.07.004 [doi] AB - BACKGROUND AND AIMS: A drug interaction between infliximab and azathioprine has previously been reported in Crohn's disease patients: the concentration of the main active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), increased 1-3 weeks after the first infliximab infusion by 50% compared to baseline. The aim of this prospective study was to determine the effect of adalimumab on thiopurine metabolism in Crohn's disease patients, evaluated by 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR) concentration measurement. METHODS: Crohn's disease patients on azathioprine or mercaptopurine maintenance therapy starting with concomitant adalimumab treatment were included. 6-TGN and 6-MMPR concentrations were determined before initiation of adalimumab and after 2, 4, 6 and 12 weeks of combination therapy. The activity of three essential enzymes involving thiopurine metabolism, thiopurine S-methyltransferase (TPMT), hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and inosine-triphosphate pyrophosphatase (ITPase), was evaluated at baseline and week 4. Clinical outcome was evaluated by the Crohn's disease activity index and C-reactive protein concentrations at baseline, week 4 and week 12. RESULTS: Twelve Crohn's disease patients were analyzed. During the follow-up period of 12 weeks the median 6-TGN and 6-MMPR concentrations did not significantly change compared to baseline. TPMT, ITPase and HGPRT enzyme activity did not change either after 4 weeks. In two patients (17%) myelotoxicity was observed within 2-4 weeks, in whom both low therapeutic 6-TGN and 6-MMPR concentrations were found. CONCLUSIONS: In this study in Crohn's disease patients no pharmacokinetic interaction was shown between adalimumab and the conventional thiopurines, azathioprine and mercaptopurine. CI - (c) 2013. FAU - Wong, D R AU - Wong DR AD - Department of Clinical Pharmacy & Toxicology, Orbis Medical Centre, Sittard, The Netherlands. Electronic address: d.wong@orbisconcern.nl. FAU - Pierik, M AU - Pierik M AD - Department of Gastroenterology and Hepatology, University Hospital Maastricht, Maastricht, The Netherlands. FAU - Seinen, M L AU - Seinen ML AD - Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands. FAU - van Bodegraven, A A AU - van Bodegraven AA AD - Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands. FAU - Gilissen, L P L AU - Gilissen LP AD - Department of Gastroenterology and Hepatology, Catharina Hospital, Eindhoven, The Netherlands. FAU - Bus, P AU - Bus P AD - Department of Gastroenterology, Laurentius Hospital, Roermond, The Netherlands. FAU - Bakker, J A AU - Bakker JA AD - Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Centre, Leiden, The Netherlands. FAU - Masclee, A A M AU - Masclee AA AD - Department of Gastroenterology and Hepatology, University Hospital Maastricht, Maastricht, The Netherlands. FAU - Neef, C AU - Neef C AD - Department of Clinical Pharmacy & Toxicology, University Hospital Maastricht, Maastricht, The Netherlands; Department of Toxicology, Maastricht University, CAPHRI School for Public Health and Primary Care, Maastricht, The Netherlands. FAU - Engels, L G J B AU - Engels LG AD - Department of Gastroenterology, Orbis Medical Centre, Sittard, The Netherlands. FAU - Hooymans, P M AU - Hooymans PM AD - Department of Clinical Pharmacy & Toxicology, Orbis Medical Centre, Sittard, The Netherlands. LA - eng PT - Journal Article DEP - 20130807 PL - England TA - J Crohns Colitis JT - Journal of Crohn's & colitis JID - 101318676 RN - 0 (Anti-Inflammatory Agents, Non-Steroidal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Guanine Nucleotides) RN - 0 (Immunosuppressive Agents) RN - 0 (Thionucleotides) RN - 15867-02-4 (6-thioguanylic acid) RN - 46S541971T (Thioinosine) RN - 7021-52-5 (6-methylthiopurine ribonucleoside-5'-phosphate) RN - 9007-41-4 (C-Reactive Protein) RN - EC 2.1.1.- (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 2.4.2.8 (Hypoxanthine Phosphoribosyltransferase) RN - EC 3.6.1.- (Pyrophosphatases) RN - FYS6T7F842 (Adalimumab) RN - MRK240IY2L (Azathioprine) SB - IM MH - Adalimumab MH - Adolescent MH - Adult MH - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology/therapeutic use MH - Antibodies, Monoclonal, Humanized/*pharmacology/therapeutic use MH - Azathioprine/*metabolism/pharmacokinetics/therapeutic use MH - C-Reactive Protein/metabolism MH - Crohn Disease/drug therapy/*metabolism MH - Drug Interactions MH - Drug Therapy, Combination MH - Erythrocytes/enzymology MH - Female MH - Guanine Nucleotides/blood MH - Humans MH - Hypoxanthine Phosphoribosyltransferase/blood MH - Immunosuppressive Agents/*metabolism/pharmacokinetics/therapeutic use MH - Male MH - Methyltransferases/blood MH - Middle Aged MH - Prospective Studies MH - Pyrophosphatases/blood MH - Severity of Illness Index MH - Thioinosine/analogs & derivatives/blood MH - Thionucleotides/blood MH - Young Adult MH - Inosine Triphosphatase OTO - NOTNLM OT - 6-MMPR OT - 6-MP OT - 6-TGN OT - 6-TGTP OT - 6-methylmercaptopurine ribonucleotides OT - 6-thioguanine nucleotides OT - 6-thioguanine triphosphate OT - 95% CI OT - 95% confidence interval OT - AZA OT - Adalimumab OT - Azathioprine OT - C-reactive protein OT - CD OT - CDAI OT - CRP OT - Crohn's disease OT - Crohn's disease activity index OT - Drug interaction OT - HGPRT OT - HPLC OT - IBD OT - IMP OT - ITPase OT - MCV OT - Mercaptopurine OT - RBC OT - TDM OT - TPMT OT - Therapeutic drug monitoring OT - UC OT - azathioprine OT - high performance liquid chromatography OT - hypoxanthine-guanine phosphoribosyl transferase OT - inflammatory bowel disease OT - inosine monophosphate OT - inosine triphosphate pyrophosphatase OT - mean corpuscular volume OT - mercaptopurine OT - red blood cells OT - therapeutic drug monitoring OT - thiopurine S-methyltransferase OT - ulcerative colitis EDAT- 2013/08/13 06:00 MHDA- 2014/10/18 06:00 CRDT- 2013/08/13 06:00 PHST- 2013/02/17 00:00 [received] PHST- 2013/07/01 00:00 [revised] PHST- 2013/07/09 00:00 [accepted] PHST- 2013/08/13 06:00 [entrez] PHST- 2013/08/13 06:00 [pubmed] PHST- 2014/10/18 06:00 [medline] AID - S1873-9946(13)00242-0 [pii] AID - 10.1016/j.crohns.2013.07.004 [doi] PST - ppublish SO - J Crohns Colitis. 2014 Feb;8(2):120-8. doi: 10.1016/j.crohns.2013.07.004. Epub 2013 Aug 7.