PMID- 37993078 OWN - NLM STAT- MEDLINE DCOM- 20231225 LR - 20240129 IS - 1872-7786 (Electronic) IS - 0009-2797 (Linking) VI - 387 DP - 2024 Jan 5 TI - Ciprofol is primarily glucuronidated by UGT1A9 and predicted not to cause drug-drug interactions with typical substrates of CYP1A2, CYP2B6, and CYP2C19. PG - 110811 LID - S0009-2797(23)00478-7 [pii] LID - 10.1016/j.cbi.2023.110811 [doi] AB - Ciprofol is a novel intravenous anesthetic agent. Its major glucuronide metabolite, M4, is found in plasma and urine. However, the specific isoforms of UDP-glucuronosyltransferases (UGTs) that metabolize ciprofol to M4 remain unknown. This study systematically characterized UGTs that contribute to the formation of M4 using human liver microsomes (HLM), human intestinal microsomes (HIM), and human recombinant UGTs. The inhibitory potential of ciprofol and M4 against major human UGTs and cytochrome P450 enzymes (P450s) was also explored. In vitro-in vivo extrapolation (IVIVE) and physiologically-based pharmacokinetic (PBPK) simulations were performed to predict potential in vivo drug-drug interactions (DDIs) caused by ciprofol. Glucuronidation of ciprofol followed Michaelis-Menten kinetics in both HLM and HIM with apparent K(m) values of 345 and 412 muM, V(max) values of 2214 and 444 nmol min(-1).mg protein(-1), respectively. The in vitro intrinsic clearances (CL(int) = V(max)/K(m)) for ciprofol glucuronidation by HLM and HIM were 6.4 and 1.1 muL min(-1).mg protein(-1), respectively. Human recombinant UGT studies revealed that UGT1A9 is the predominant isoform mediating M4 formation, followed by UGT1A7, with UGT1A8 playing a minor role. Ciprofol competitively inhibited CYP1A2 (K(i) = 12 muM) and CYP2B6 (K(i) = 4.7 muM), and noncompetitively inhibited CYP2C19 (K(i) = 29 muM). No time-dependent inhibition by ciprofol was noted for CYP1A2, CYP2B6, or CYP2C19. In contrast, M4 showed limited or no inhibitory effects against selected P450s. Neither ciprofol nor M4 inhibited UGTs significantly. Initial IVIVE suggested potential ciprofol-mediated inhibition of CYP1A2, CYP2B6, and CYP2C19 inhibition in vivo. However, PBPK simulations showed no significant effect on phenacetin, bupropion, and S-mephenytoin exposure or peak plasma concentration. Our findings are pertinent for future DDI studies of ciprofol as either a perpetrator or victim drug. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Hou, Lei AU - Hou L AD - Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. FAU - Zhao, Yingying AU - Zhao Y AD - Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. FAU - Zhao, Shiyu AU - Zhao S AD - Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. FAU - Zhang, XueXia AU - Zhang X AD - Institute of Chinese Medicine, Henan Academy of Chinese Medicine, Zhengzhou, China. FAU - Yao, Xia AU - Yao X AD - Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. FAU - Yang, Jianjun AU - Yang J AD - Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. FAU - Wang, Ziteng AU - Wang Z AD - Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore. FAU - Chan, Eric Chun Yong AU - Chan ECY AD - Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore. FAU - Liu, Shuaibing AU - Liu S AD - Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: fccliusb@zzu.edu.cn. LA - eng PT - Journal Article DEP - 20231120 PL - Ireland TA - Chem Biol Interact JT - Chemico-biological interactions JID - 0227276 RN - EC 1.14.14.1 (Cytochrome P-450 CYP2B6) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A2) RN - EC 1.14.14.1 (Cytochrome P-450 CYP2C19) RN - EC 2.4.1.17 (Glucuronosyltransferase) RN - EC 1.14.14.1 (CYP2B6 protein, human) RN - EC 1.14.14.1 (CYP2C19 protein, human) RN - EC 1.14.14.1 (CYP1A2 protein, human) SB - IM MH - Humans MH - Cytochrome P-450 CYP2B6/metabolism MH - *Cytochrome P-450 CYP1A2/metabolism MH - Cytochrome P-450 CYP2C19/metabolism MH - *Microsomes, Liver/metabolism MH - Glucuronosyltransferase/metabolism MH - Drug Interactions MH - Kinetics OTO - NOTNLM OT - Ciprofol OT - Cytochrome P450 enzymes OT - Inhibition OT - Physiologically-based pharmacokinetic OT - UDP-Glucuronosyltransferases COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/11/23 00:42 MHDA- 2023/12/25 06:41 CRDT- 2023/11/22 19:33 PHST- 2023/07/17 00:00 [received] PHST- 2023/11/14 00:00 [revised] PHST- 2023/11/16 00:00 [accepted] PHST- 2023/12/25 06:41 [medline] PHST- 2023/11/23 00:42 [pubmed] PHST- 2023/11/22 19:33 [entrez] AID - S0009-2797(23)00478-7 [pii] AID - 10.1016/j.cbi.2023.110811 [doi] PST - ppublish SO - Chem Biol Interact. 2024 Jan 5;387:110811. doi: 10.1016/j.cbi.2023.110811. Epub 2023 Nov 20.