PMID- 30451390 OWN - NLM STAT- MEDLINE DCOM- 20190920 LR - 20190920 IS - 1742-7843 (Electronic) IS - 1742-7835 (Linking) VI - 124 IP - 5 DP - 2019 May TI - Red Blood cell IMPDH activity in adults and children with or without azathioprine: Relationship between thiopurine metabolites, ITPA and TPMT activities. PG - 600-606 LID - 10.1111/bcpt.13176 [doi] AB - Inosine monophosphate dehydrogenase (IMPDH) is considered as the limiting enzyme of thiopurine metabolism for the formation of 6-thioguanine nucleotides (6-TGN). No data are available on the influence of RBC IMPDH activity on the metabolism of thiopurine drugs in individuals with IBD. The aims of this study were as follows: (a) to carry out a phenotypic study of RBC IMPDH activity in adults and children treated or not with azathioprine (AZA) for autoimmune diseases, and (b) to investigate the relationship between the activities of IMPDH, thiopurine metabolites, inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT). IMPDH activity was determined in 97 adults and 67 children treated or not with AZA. 6-Thioguanine nucleotides (6-TGN), 6-methylmercaptopurine nucleotide (6-MeMPN) levels, and ITPA as well as TPMT activities were measured in RBCs by HPLC. Using the Gaussian mixture model, distribution of IMPDH activity was evaluated. Influence of age, sex and AZA treatment on IMPDH activity was also assessed. A bimodal distribution in IMPDH activity was found with 87% of patients exhibiting normal activity and 13% of patients with high activity. No influence of age, sex and AZA therapy was found. There is no relationship between TPMT, ITPA and IMPDH activities. A negative correlation between IMPDH activity and 6-MeMPN was shown in adults and children (rs = -0.335 P = 0.014 and rs = -0.383 P = 0.012, respectively). Our results suggest that AZA-treated patients exhibiting lower IMPDH activity could have higher Me-6MPN levels with higher risk of hepatotoxicity. We demonstrated that RBC matrix could be an interesting alternative to lymphocyte matrix to monitor thiopurine metabolites and enzyme activity. CI - (c) 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). FAU - Citterio-Quentin, Antony AU - Citterio-Quentin A AD - Clinical Pharmacy, Pharmacokinetics and Drug Evaluation, Universite de Lyon, Universite Lyon 1, France. AD - Edouard Herriot Hospital, Laboratory of Medical Biology Multisites of University Hospital of Lyon, Pharmaco-Toxicology Unit, Hospices Civils de Lyon, Lyon, France. FAU - El Mahmoudi, Amal AU - El Mahmoudi A AD - Clinical Pharmacy, Pharmacokinetics and Drug Evaluation, Universite de Lyon, Universite Lyon 1, France. AD - Edouard Herriot Hospital, Laboratory of Medical Biology Multisites of University Hospital of Lyon, Pharmaco-Toxicology Unit, Hospices Civils de Lyon, Lyon, France. FAU - Perret, Thibault AU - Perret T AD - Clinical Pharmacy, Pharmacokinetics and Drug Evaluation, Universite de Lyon, Universite Lyon 1, France. AD - Edouard Herriot Hospital, Laboratory of Medical Biology Multisites of University Hospital of Lyon, Pharmaco-Toxicology Unit, Hospices Civils de Lyon, Lyon, France. FAU - Conway, Anthony AU - Conway A AD - Clinical Pharmacy, Pharmacokinetics and Drug Evaluation, Universite de Lyon, Universite Lyon 1, France. AD - School of Pharmacy and Pharmaceuticals Sciences, Trinity College Dublin, Dublin, Ireland. FAU - Ryan, Aishling AU - Ryan A AD - Clinical Pharmacy, Pharmacokinetics and Drug Evaluation, Universite de Lyon, Universite Lyon 1, France. AD - School of Pharmacy and Pharmaceuticals Sciences, Trinity College Dublin, Dublin, Ireland. FAU - Beringer, Audrey AU - Beringer A AD - Clinical Pharmacy, Pharmacokinetics and Drug Evaluation, Universite de Lyon, Universite Lyon 1, France. AD - Edouard Herriot Hospital, Laboratory of Medical Biology Multisites of University Hospital of Lyon, Pharmaco-Toxicology Unit, Hospices Civils de Lyon, Lyon, France. FAU - Lachaux, Alain AU - Lachaux A AD - Pediatric Gastroenterology Unit, Hopital Femme Mere Enfant (HFME), Lyon, France. FAU - Boulieu, Roselyne AU - Boulieu R AD - Clinical Pharmacy, Pharmacokinetics and Drug Evaluation, Universite de Lyon, Universite Lyon 1, France. AD - Edouard Herriot Hospital, Laboratory of Medical Biology Multisites of University Hospital of Lyon, Pharmaco-Toxicology Unit, Hospices Civils de Lyon, Lyon, France. LA - eng PT - Journal Article DEP - 20181228 PL - England TA - Basic Clin Pharmacol Toxicol JT - Basic & clinical pharmacology & toxicology JID - 101208422 RN - EC 1.1.1.205 (IMP Dehydrogenase) RN - EC 2.1.1.- (Methyltransferases) RN - EC 2.1.1.67 (TPMT protein, human) RN - EC 3.6.1.- (Pyrophosphatases) RN - EC 3.6.1.9 (ITPA protein, human) RN - MRK240IY2L (Azathioprine) SB - IM MH - Adolescent MH - Adult MH - Age Factors MH - Aged MH - Aged, 80 and over MH - Autoimmune Diseases/*blood/*drug therapy/enzymology MH - Azathioprine/adverse effects/*therapeutic use MH - Child MH - Child, Preschool MH - Erythrocytes/drug effects/*enzymology MH - Female MH - Humans MH - IMP Dehydrogenase/*blood MH - Male MH - Methyltransferases/*blood MH - Middle Aged MH - Pyrophosphatases/*blood MH - Retrospective Studies EDAT- 2018/11/20 06:00 MHDA- 2019/09/21 06:00 CRDT- 2018/11/20 06:00 PHST- 2018/05/30 00:00 [received] PHST- 2018/11/11 00:00 [accepted] PHST- 2018/11/20 06:00 [pubmed] PHST- 2019/09/21 06:00 [medline] PHST- 2018/11/20 06:00 [entrez] AID - 10.1111/bcpt.13176 [doi] PST - ppublish SO - Basic Clin Pharmacol Toxicol. 2019 May;124(5):600-606. doi: 10.1111/bcpt.13176. Epub 2018 Dec 28.