@article {Jonesdmd.117.077776, author = {Barry C Jones and Roshini Markandu and Chungang Gu and Graeme Scarfe}, title = {CYP-mediated sulfoximine de-imination of AZD6738}, elocation-id = {dmd.117.077776}, year = {2017}, doi = {10.1124/dmd.117.077776}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {In hepatic S9 and human liver microsomes (HLM) the sulfoximine moiety of the ATR inhibitor AZD6738 is metabolised to its corresponding sulfoxide (AZ8982) and sulfone (AZ0002). The initial de-imination to AZ8982 is nominally a reductive reaction but in HLM required NADPH and was inhibited by 1-aminobenzotriazole (ABT) at 1mM. Studies in a panel of 11 recombinant cytochrome P450s (CYPs) - CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 CYP2J2, CYP3A4 and CYP3A5 - confirmed that the de-imination was an oxidative process, mediated largely by CYP2C8 with some CYP2J2 involvement, whilst the subsequent oxidation to the sulfone was carried out largely by CYP2J2, CYP3A4 and CYP3A5. There was no measureable metabolism in flavin-containing monooxygenase (FMO) enzymes FMO3, FMO5 or NADPH cytochrome C reductase. Studies using SilensomesTM, a commercially available HLM where specific CYPs have been inhibited by selective mechanism-based inhibitors, showed that when CYP2C8 was inhibited the rate of de-imination was reduced by 95\% suggesting that CYP2J2 is only playing a minor role in HLM. When CYP3A4 was inhibited the rate increased by 58\% due to the inhibition of the subsequent sulfone formation. Correlation studies in HLM samples from different individuals confirmed the role of CYP2C8 in the de-imination over CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A. Hence, although nominally a reduction, the de-imination of AZD6738 to its sulfoxide metabolite AZ8982 is an oxidation mediated by CYP2C8 and that this metabolite is subsequently oxidised to the sulfone (AZ0002) largely by CYP3A.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2017/08/23/dmd.117.077776}, eprint = {https://dmd.aspetjournals.org/content/early/2017/08/23/dmd.117.077776.full.pdf}, journal = {Drug Metabolism and Disposition} }