Wu W N, McKown L A, Kuo G H
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Route 202, Raritan, NJ 08869, USA.
Eur J Drug Metab Pharmacokinet. 2005 Jan-Jun;30(1-2):113-20. doi: 10.1007/BF03226416.
The in vitro and in vivo metabolism of RWJ-69442, an alpha-1A-adrenergic receptor antagonist, was investigated after incubation with rat, dog, and human hepatic S9 fractions in the presence of NADPH-generating system, and a single oral/iv dose administration to rats (oral: 100 mg/kg; iv: 10 mg/kg). Unchanged RWJ-69442 (> or =30% of the sample in vitro; < or =47% of the sample in vivo) plus 14 metabolites were profiled, quantified and tentatively identified on the basis of API-MS and MS/MS data. The metabolic pathways for RWJ-69442 are proposed via the 4 steps: 1. phenyl/piperazinylhydroxylation, 2. N/O-dealkylation, 3. N-dephenylation, and 4. dehydration. Pathway 1 formed OH-phenyl-RWJ-69442 (M1, 4-32% in vitro & in vivo), and diOH-RWJ-69442 (M4, <1-4% in vitro & in vivo). Pathway 2 generated O-desisopropyl-RWJ-69442 (M2, <1-21% in vitro & in vivo), N-desmethyl-RWJ-69442 (M3, 2-3% in vitro & in vivo), N-desmethyl-M2 (M6, 1-8% in vitro & in vivo), and N-dealkylated RWJ-69442 (M9, < or =1-17% in vitro & in vivo), and in conjunction with pathway 1 produced 6 minor to major oxidized metabolites, OH-M2 (M5, 1-2% in vitro), OH-M3 (M11, 4-6% in vivo), OH-M9 (M10, <1-34% in vitro & in vivo), O-desisopropyl-M9 (M12, 3-21% in vivo), O-desisopropyl-M10 (M13,2-12% in vivo), and dehydro-M13 (M14, 25% in vivo). Pathways 3 and 4 formed 2 minor metabolites, N-desphenyl-RWJ-69442 (M7, <1-12% in vitro & in vivo) and dehydrated-RWJ-69442 (M8, <1-2% in vitro), respectively. RWJ-69442 is extensively metabolized in vitro in the rat and human (except dog), and in vivo in the rat.
在存在NADPH生成系统的情况下，将α-1A肾上腺素能受体拮抗剂RWJ-69442与大鼠、犬和人肝脏S9组分一起孵育，并对大鼠进行单次口服/静脉给药（口服：100 mg/kg；静脉：10 mg/kg）后，研究了其体内外代谢情况。根据API-MS和MS/MS数据，对未变化的RWJ-69442（体外样品中≥30%；体内样品中≤47%）以及14种代谢物进行了分析、定量和初步鉴定。提出RWJ-69442的代谢途径包括4个步骤：1. 苯基/哌嗪基羟基化；2. N/O-脱烷基化；3. N-脱苯基化；4. 脱水。途径1形成OH-苯基-RWJ-69442（M1，体外和体内为4-32%）和二羟基-RWJ-69442（M4，体外和体内＜1-4%）。途径2产生O-去异丙基-RWJ-69442（M2，体外和体内＜1-21%）、N-去甲基-RWJ-69442（M3，体外和体内为2-3%）、N-去甲基-M2（M6，体外和体内为1-8%）以及N-脱烷基化RWJ-69442（M9，体外和体内≤1-17%），并且与途径1一起产生了6种从少量到大量的氧化代谢物，OH-M2（M5，体外为1-2%）、OH-M3（M11，体内为4-6%）、OH-M9（M10，体外和体内＜1-34%）、O-去异丙基-M9（M12，体内为3-21%）、O-去异丙基-M10（M13，体内为2-12%）以及脱氢-M13（M14，体内为25%）。途径3和4分别形成2种少量代谢物，N-脱苯基-RWJ-69442（M7，体外和体内＜1-12%）和脱水-RWJ-69442（M8，体外＜1-2%）。RWJ-69442在大鼠和人（犬除外）的体外以及大鼠的体内均被广泛代谢。
