Shukla U A, Marathe P H, Pittman K A, Barbhaiya R H
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, NY 13221.
Drug Metab Dispos. 1993 May-Jun;21(3):502-7.
In a two-way crossover study, the pharmacokinetics and disposition of nefazodone (NEF) were investigated after intravenous (i.v.) infusion and oral (po) gavage of a solution of 10 mg/kg (5 microCi/kg) of [14C]NEF to four beagle dogs. Plasma was analyzed by HPLC for NEF, and its metabolites hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP), and p-hydroxynefazodone (p-HO-NEF). Plasma, urine, and feces were also analyzed for total radioactivity. Mean AUC(INF) values for NEF after po administration were about an order of magnitude lower compared with those after i.v. administration. Mean Cmax and AUC(INF) values for the metabolites after po administration were about as high or higher compared with those after i.v. administration. Mean (SD) total body clearance of NEF was 1.56 (0.34) liter/hr.kg-1, and mean (SD) steady-state volume of distribution of NEF was 3.24 (1.0) liter/kg. Mean (SD) absolute bioavailability of NEF after po administration was calculated to be 14.0 (4.2)%. The fraction of oral NEF eliminated presystemically was estimated to be 86%. Plasma concentration-time profiles for total radioactivity after i.v. and po administration were superimposable. The recovery of total radioactivity in urine and feces was similar after iv and po administration, indicating complete absorption of the drug after po administration. NEF, HO-NEF, and p-HO-NEF accounted for approximately 37% and 12% of the plasma AUC for total radioactivity following i.v. and po administration, respectively. The total urinary (28%) and fecal (61%) recovery after i.v. or po administration was approximately 90% of the dose within 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)
在一项双向交叉研究中，对4只比格犬静脉输注和口服灌胃10mg/kg（5μCi/kg）的[14C]奈法唑酮（NEF）溶液后，研究了NEF的药代动力学和处置情况。通过高效液相色谱法分析血浆中的NEF及其代谢产物羟基奈法唑酮（HO-NEF）、间氯苯哌嗪（mCPP）和对羟基奈法唑酮（p-HO-NEF）。还分析了血浆、尿液和粪便中的总放射性。口服给药后NEF的平均AUC(INF)值比静脉给药后低约一个数量级。口服给药后代谢产物的平均Cmax和AUC(INF)值与静脉给药后大致相同或更高。NEF的平均（标准差）全身清除率为1.56（0.34）升/小时·千克-1，NEF的平均（标准差）稳态分布容积为3.24（1.0）升/千克。口服给药后NEF的平均（标准差）绝对生物利用度经计算为14.0（4.2）%。口服NEF经体前消除的比例估计为86%。静脉注射和口服给药后总放射性的血浆浓度-时间曲线可重叠。静脉注射和口服给药后尿液和粪便中总放射性的回收率相似，表明口服给药后药物完全吸收。静脉注射和口服给药后，NEF、HO-NEF和p-HO-NEF分别占血浆总放射性AUC的约37%和12%。静脉注射或口服给药后7天内，尿液（28%）和粪便（61%）的总回收率约为给药剂量的90%。（摘要截短至250字）
