PMID- 35569194 OWN - NLM STAT- MEDLINE DCOM- 20220726 LR - 20220728 IS - 1880-0920 (Electronic) IS - 1347-4367 (Linking) VI - 45 DP - 2022 Aug TI - Intestinal microbiota-mediated biotransformations alter the pharmacokinetics of the major metabolites of azathioprine in rats after oral administration. PG - 100458 LID - S1347-4367(22)00015-5 [pii] LID - 10.1016/j.dmpk.2022.100458 [doi] AB - Adverse reactions to azathioprine (AZA) vary greatly among individuals, which is associated with the variable levels of its major metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). The intestinal microbiota has been proven to contain AZA-metabolizing enzymes, although the explicit role of the intestinal microbiota in AZA metabolism in vivo remains poorly comprehended. In this study, the pharmacokinetic behaviours of 6-TGN and 6-MMP were assessed in the pseudo germ-free (PGF) group and control group following oral administration of AZA. The AUC(0-t) and C(max) of 6-TGN in the PGF group were significantly decreased by 34.0% and 35.0% (P < 0.05) compared with those in the control group. Additionally, the AUC(0-t) and C(max) of 6-MMP were reduced by 27.9% and 34.2% in the PGF group, although the differences were not significant. The TPMT and NUDT15 genotypes of rats in the two groups were genetically identical. The expression levels of key AZA-metabolizing enzymes in liver were not different between two groups. Furthermore, the major metabolites of AZA in the incubation system with intestinal microbial enzymes were identified. In summary, shifts in the composition of the intestinal microbiota may regulate the exposure of 6-TGN in vivo by altering the gut microbial metabolism of AZA. CI - Copyright (c) 2022. Published by Elsevier Ltd. FAU - Wang, Shanshan AU - Wang S AD - Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, PR China. FAU - Qin, Yan AU - Qin Y AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China. FAU - Wen, Qiuyu AU - Wen Q AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China; Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, PR China. FAU - Xia, Quan AU - Xia Q AD - Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, PR China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230032, PR China. FAU - Gu, Ruoyu AU - Gu R AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China. FAU - Wang, Sheng AU - Wang S AD - Center for Scientific Research of Anhui Medical University, Hefei, 230032, PR China. FAU - Chen, GuanJun AU - Chen G AD - Center for Scientific Research of Anhui Medical University, Hefei, 230032, PR China. FAU - Tan, Chao AU - Tan C AD - Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, PR China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230032, PR China. FAU - Shen, Chenlin AU - Shen C AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China; Hefei Kaifan Analytical Technology Co., Ltd., Hefei, 230051, PR China. Electronic address: shchlin520@126.com. FAU - Song, Shuai AU - Song S AD - Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, PR China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China; The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230032, PR China. Electronic address: vae0558@163.com. LA - eng PT - Journal Article DEP - 20220319 PL - England TA - Drug Metab Pharmacokinet JT - Drug metabolism and pharmacokinetics JID - 101164773 RN - MRK240IY2L (Azathioprine) SB - IM MH - Administration, Oral MH - Animals MH - *Azathioprine/pharmacokinetics MH - Biotransformation MH - *Gastrointestinal Microbiome MH - Rats OTO - NOTNLM OT - Azathioprine OT - Intestinal microbiota OT - Metabolism OT - Pharmacokinetics OT - Pseudo germ-free rats EDAT- 2022/05/16 06:00 MHDA- 2022/07/27 06:00 CRDT- 2022/05/15 18:06 PHST- 2021/09/29 00:00 [received] PHST- 2022/02/24 00:00 [revised] PHST- 2022/03/11 00:00 [accepted] PHST- 2022/05/16 06:00 [pubmed] PHST- 2022/07/27 06:00 [medline] PHST- 2022/05/15 18:06 [entrez] AID - S1347-4367(22)00015-5 [pii] AID - 10.1016/j.dmpk.2022.100458 [doi] PST - ppublish SO - Drug Metab Pharmacokinet. 2022 Aug;45:100458. doi: 10.1016/j.dmpk.2022.100458. Epub 2022 Mar 19.