Wu Wu-Nan, McKown Linda A, Reitz Allen B
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, PA 19477, USA.
Eur J Drug Metab Pharmacokinet. 2006 Oct-Dec;31(4):277-83. doi: 10.1007/BF03190468.
The in vitro and in vivo metabolism of RWJ-53050, an anxiolytic agent, was investigated after incubation with rat and human hepatic S9 fractions, and human microsomes and 7 microsomes containing individual human CYP isoforms, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 in the presence of NADPH-generating system, and a single oral dose administration to dogs (30 mg/kg). Unchanged RWJ-53050 (> or = 74% of the sample in vitro; < or = 13% in vivo) plus 16 metabolites were profiled, quantified and tentatively identified based on the API-MS and MS/MS data. The formation of RWJ-53050 metabolites are via the 5 pathways: 1. N/O-demethylation, 2. phenylhydroxylation, 3. pyrido-oxidation, 4. dehydration, and 5. conjugation. Pathway 1 formed O-desmethyl-phenyl-RWJ-53050 (M1, < 1-12% in vitro & in vivo), O-desmethyl-benzimidazole-RWJ-53050 (M2), and N-desmethyl-RWJ-53050 (M3) (M2 & M3, < or = 3% in vitro & in vivo). Pathway 2 generated hydroxy-benzimidazole-RWJ-53050 (M4), hydroxy-phenyl-RWJ-53050 (M5), and hydroxy-phenyl-M4 (M9) (< or = 3% in vitro & in vivo). Pathway 3 formed 2 trace oxidized metabolites, hydroxy-pyrido-RWJ-53050 (M6, < or = 1% in vitro) and oxo-pyrido-RWJ-53050 (M8, < 1% in vitro) and in conjunction with pathway 1 produced 2 trace dioxidized metabolites, OH-benzimidazole-M6 (M10) and OH-benzimidazole-M8 (M11) (in vitro). Pathway 4 formed a minor dehydrated metabolite of M6 (M7, 3%, in vitro). Pathway 5 produced 3 in vivo conjugates, M1-glucuronide (M14, 17%), M5-glucuronide (M15, 50%), and M5-sulfate (M16, 10%). RWJ-53050 is substantially metabolized in vitro in the rat and human, and extensively metabolized in vivo in the dog. CYP1A2, CYP3A4 and CYP2D6 are responsible for the formation of oxidized metabolites, M1, M2, M4, M5 and M9.
在与大鼠和人肝脏S9组分、人微粒体以及含有个体人细胞色素P450(CYP)同工酶CYP1A2、CYP2A6、CYP2C9、CYP2C19、CYP2D6、CYP2E1和CYP3A4的7种微粒体在有NADPH生成系统存在的情况下温育后,以及对犬单次口服给药(30mg/kg)后,研究了抗焦虑药RWJ - 53050的体外和体内代谢情况。基于API - MS和MS/MS数据,对未变化的RWJ - 53050(体外≥74%的样品;体内≤13%)以及16种代谢物进行了分析、定量和初步鉴定。RWJ - 53050代谢物的形成通过5条途径:1. N/O - 去甲基化;2. 苯基羟基化;3. 吡啶氧化;4. 脱水;5. 结合。途径1形成O - 去甲基 - 苯基 - RWJ - 53050(M1,体外和体内<1 - 12%)、O - 去甲基 - 苯并咪唑 - RWJ - 53050(M2)和N - 去甲基 - RWJ - 53050(M3)(M2和M3,体外和体内≤3%)。途径2产生羟基 - 苯并咪唑 - RWJ - 53050(M4)、羟基 - 苯基 - RWJ - 53050(M5)和羟基 - 苯基 - M4(M9)(体外和体内≤3%)。途径3形成2种痕量氧化代谢物,羟基 - 吡啶 - RWJ - 53050(M6,体外≤1%)和氧代 - 吡啶 - RWJ - 53050(M8,体外<1%),并且与途径1一起产生2种痕量二氧化代谢物,OH - 苯并咪唑 - M6(M10)和OH - 苯并咪唑 - M8(M11)(体外)。途径4形成M6的一种少量脱水代谢物(M7,体外3%)。途径5产生3种体内结合物,M1 - 葡糖醛酸苷(M14,17%)、M5 - 葡糖醛酸苷(M15,50%)和M5 - 硫酸盐(M16,10%)。RWJ - 53050在大鼠和人中体外大量代谢,在犬体内广泛代谢。CYP1A2、CYP3A4和CYP2D6负责氧化代谢物M1、M2、M4、M5和M9的形成。