Vermeir Marc, Naessens Ineke, Remmerie Bart, Mannens Geert, Hendrickx Jan, Sterkens Patrick, Talluri Krishna, Boom Sandra, Eerdekens Marielle, van Osselaer Nancy, Cleton Adriaan
Johnson & Johnson Pharmaceutical Research and Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Drug Metab Dispos. 2008 Apr;36(4):769-79. doi: 10.1124/dmd.107.018275. Epub 2008 Jan 28.
Absorption, metabolism, and excretion of paliperidone, an atypical antipsychotic, was studied in five healthy male subjects after a single dose of 1 mg of [(14)C]paliperidone oral solution ( approximately 16 microCi/subject). One week after dosing, 88.4 to 93.8% (mean 91.1%) of the administered radioactivity was excreted: 77.1 to 87.1% (mean 79.6%) in urine and 6.8 to 14.4% (mean 11.4%) in the feces. Paliperidone was the major circulating compound (97% of the area under the plasma concentration-time curve at 24 h). No metabolites could be detected in plasma. Renal excretion was the major route of elimination with 59% of the dose excreted unchanged in urine. About half of the renal excretion occurred by active secretion. Unchanged drug was not detected in feces. Four metabolic pathways were identified as being involved in the elimination of paliperidone, each of which accounted for up to a maximum of 6.5% of the biotransformation of the total dose. Biotransformation of the drug occurred through oxidative N-dealkylation (formation of the acid metabolite M1), monohydroxylation of the alicyclic ring (M9), alcohol dehydrogenation (formation of the ketone metabolite M12), and benzisoxazole scission (formation of M11), the latter in combination with glucuronidation (M16) or alicyclic hydroxylation (M10). Unchanged drug, M1, M9, M12, and M16 were detected in urine; M10 and M11 were detected in feces. The monohydroxylated metabolite M9 was solely present in urine samples of extensive CYP2D6 metabolizers, whereas M10, another metabolite monohydroxylated at the alicyclic ring system, was present in feces of poor metabolizers as well. In conclusion, paliperidone is not metabolized extensively and is primarily renally excreted.
在5名健康男性受试者单次口服1毫克[(14)C]帕利哌酮口服溶液（约16微居里/受试者）后，对非典型抗精神病药物帕利哌酮的吸收、代谢和排泄情况进行了研究。给药一周后，88.4%至93.8%（平均91.1%）的给药放射性被排出：77.1%至87.1%（平均79.6%）通过尿液排出，6.8%至14.4%（平均11.4%）通过粪便排出。帕利哌酮是主要的循环化合物（24小时时血浆浓度 - 时间曲线下面积的97%）。血浆中未检测到代谢物。肾脏排泄是主要的消除途径，59%的剂量以原形经尿液排出。约一半的肾脏排泄通过主动分泌发生。粪便中未检测到原形药物。已确定有四条代谢途径参与帕利哌酮的消除，每条途径占总剂量生物转化的比例最高可达6.5%。药物的生物转化通过氧化N - 去烷基化（形成酸性代谢物M1）、脂环族环的单羟基化（M9）、醇脱氢（形成酮代谢物M12）和苯并异恶唑断裂（形成M11）进行，后者与葡萄糖醛酸化（M16）或脂环族羟基化（M10）结合。尿液中检测到原形药物、M1、M9、M12和M16；粪便中检测到M10和M11。单羟基化代谢物M9仅存在于CYP2D6广泛代谢者的尿液样本中，而另一种在脂环族环系统上单羟基化的代谢物M10也存在于代谢不良者的粪便中。总之，帕利哌酮代谢不广泛，主要经肾脏排泄。
