Gammans R E, Mayol R F, LaBudde J A
Am J Med. 1986 Mar 31;80(3B):41-51. doi: 10.1016/0002-9343(86)90331-1.
The metabolism and disposition of buspirone have been studied in the rat, the monkey, and in more than 150 human subjects. Buspirone is well absorbed, but is subject to first-pass metabolism. The mean systemic availability is approximately 4 percent. Buspirone is eliminated primarily by oxidative metabolism, which produces several hydroxylated metabolites, including 5-hydroxy-buspirone and 1-pyrimidinylpiperazine. The latter metabolite is from 1 to 20 percent as potent as buspirone in a variety of pharmacologic tests; 5-hydroxybuspirone is essentially inactive. In humans, the systemic exposure to buspirone increases linearly in relation to the oral dose. Food increases the bioavailability of buspirone by decreasing first-pass metabolism; absorption is not markedly altered. The pharmacokinetics of buspirone were not significantly different in men and women or in individuals 21 to 40 years old compared with those over 65 years of age. Half-life values observed in healthy volunteers ranged from two to 33 hours. Mean half-life values observed in healthy volunteers in the 14 studies conducted to date ranged from 2 +/- 1 to 11 +/- 3 hours. The half-life in women tended to be slightly longer than in men, but the difference was not significant. Hepatic cirrhosis resulted in a marked decrease in the clearance of buspirone, which correlated with serum alkaline phosphatase activity. Renal disease produced a modest decrease in buspirone clearance, which could not be correlated with an objective clinical measurement reflecting the severity of renal impairment. Buspirone was not removed by hemodialysis. Buspirone is highly protein bound (more than 95 percent), interacting with both albumin and alpha-acid glycoprotein. However, buspirone did not displace dilantin, propranolol, digoxin, or warfarin from plasma proteins. In rats, buspirone neither inhibited nor induced hepatic mixed-function oxidases. Co-administration of buspirone with amitriptyline or diazepam did not alter the disposition of these agents or their demethylated metabolites.
已在大鼠、猴子以及150多名人类受试者中对丁螺环酮的代谢和处置情况进行了研究。丁螺环酮吸收良好，但会经历首过代谢。平均全身生物利用度约为4%。丁螺环酮主要通过氧化代谢消除，氧化代谢会产生几种羟基化代谢物，包括5-羟基丁螺环酮和1-嘧啶基哌嗪。在各种药理试验中，后一种代谢物的效力仅为丁螺环酮的1%至20%；5-羟基丁螺环酮基本无活性。在人类中，丁螺环酮的全身暴露量与口服剂量呈线性增加关系。食物通过减少首过代谢来增加丁螺环酮的生物利用度；吸收没有明显改变。丁螺环酮的药代动力学在男性和女性之间，以及21至40岁的个体与65岁以上的个体之间没有显著差异。在健康志愿者中观察到的半衰期值范围为2至33小时。在迄今为止进行的14项研究中，健康志愿者中观察到的平均半衰期值范围为2±1至11±3小时。女性的半衰期往往比男性略长，但差异不显著。肝硬化导致丁螺环酮清除率显著降低，这与血清碱性磷酸酶活性相关。肾脏疾病使丁螺环酮清除率略有下降，这与反映肾功能损害严重程度的客观临床指标无关。丁螺环酮不能通过血液透析清除。丁螺环酮与蛋白质高度结合（超过95%），与白蛋白和α-酸性糖蛋白均有相互作用。然而，丁螺环酮不会从血浆蛋白中置换苯妥英、普萘洛尔、地高辛或华法林。在大鼠中，丁螺环酮既不抑制也不诱导肝混合功能氧化酶。丁螺环酮与阿米替林或地西泮合用不会改变这些药物及其去甲基化代谢物的处置情况。
