Furmonertinib was designed for the treatment of non-small cell lung cancer(NSCLC)patients with EGFR T790M mutation.In this study,we investigated the metabolic disposition and mass balance in humans and tissue distribution in rats.After a single oral administration of 97.9 μCi/81.5 mg[14C]-furmonertinib mesylate to six healthy male volunteers,the absorption process of furmonertinib was fast with a tmax of total plasma radioactivity at 0.75 h.Afterward,furmonertinib was extensively metabolized,with the parent drug and active metabolite AST5902 accounting for 1.68％and 0.97％of total radioactivity in plasma.The terminal t1/2 of total radioactivity in plasma was as long as 333 h,suggesting that the covalent binding of drug-related substances to plasma proteins was irreversible to a great extent.The most abundant metabolites identified in feces were desmethyl metabolite(AST5902),cysteine conjugate(M19),and parent drug(M0),which accounted for 6.28％,5.52％,and 1.38％of the dose,respectively.After intragastric administration of 124 μCi/9.93 mg/kg[14C]-furmonertinib to rats,drug-related substances were widely and rapidly distributed in tissues within 4h.The concentration of total radioactivity in the lung was 100-fold higher than that in rat plasma,which could be beneficial to the treatment of lung cancer.Mass balance in humans was achieved with 77.8％of the administered dose recovered in excretions within 35 days after administration,including 6.63％and 71.2％in urine and feces,respectively.In conclusion,[14C]-furmonertinib is completely absorbed and rapidly distributed into lung tissue,extensively metabolized in humans,presented mostly as covalent conjugates in plasma,and slowly eliminated mostly via fecal route.

Jian Meng;Hua Zhang;Jing-jing Bao;Zhen-dong Chen;Xiao-yun Liu;Yi-fan Zhang;Yong Jiang;Li-yan Miao;Da-fang Zhong

State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201210,China;The First Affiliated Hospital of Soochow University,Suzhou 215006,China;Shanghai Allist Pharmaceuticals Inc.,Shanghai 201203,China

中国药理学报（英文版）

[1]Jian Meng;Hua Zhang;Jing-jing Bao;Zhen-dong Chen;Xiao-yun Liu;Yi-fan Zhang;Yong Jiang;Li-yan Miao;Da-fang Zhong-.Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans)[J].中国药理学报（英文版）,2022(02):494-503

furmonertinib,Furmonertinib,AST5902,excretions

Metabolic,disposition,EGFR,covalent,inhibitor,humans,was,designed,treatment,small,cell,lung,cancer,NSCLC,patients,T790M,mutation,In,this,study,investigated,metabolic,mass,balance,distribution,rats,single,oral,administration,Ci,14C,mesylate,six,healthy,male,volunteers,absorption,process,fast,tmax,total,plasma,radioactivity,Afterward,extensively,metabolized,parent,drug,active,accounting,terminal,t1,long,suggesting,that,binding,related,substances,proteins,irreversible,great,extent,abundant,metabolites,identified,feces,were,desmethyl,cysteine,M19,M0,which,accounted,dose,respectively,intragastric,widely,rapidly,distributed,tissues,within,4h,concentration,fold,higher,than,could,beneficial,Mass,achieved,administered,recovered,days,after,including,urine,conclusion,completely,absorbed,into,presented,mostly,conjugates,slowly,eliminated,via,fecal,route

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