Colizza Kevin, Awad Mohamed, Kamel Amin
Exploratory Medicinal Sciences, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA.
Drug Metab Dispos. 2007 Jun;35(6):884-97. doi: 10.1124/dmd.106.014266. Epub 2007 Mar 14.
The metabolism, pharmacokinetics, and excretion of a potent and selective substance P receptor antagonist, CP-122,721 [(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzylamino)-2-phenylpiperidine], have been studied in six healthy male human subjects [four extensive metabolizers (EMs) and two poor metabolizers (PMs) of CYP2D6) following oral administration of a single 30-mg dose of [14C]CP-122,721. Approximately 84% of the administered radioactivity was recovered from the urine and feces of the subjects over a period of 312 h. Approximately 80% of the dose for EM subjects was recovered within 48 h. PM subjects, however, excreted only about 45% of the dose in 48 h and required the full 312 h to achieve nearly 80% recovery. Absorption of CP-122,721 was rapid in both extensive and poor metabolizers, as indicated by the rapid appearance of radioactivity in serum. The serum concentrations of total radioactivity were always much greater than those of unchanged drug indicating early formation of metabolites. The average CP-122,721 t1/2 was 6.7 h and 45.0 h for EM and PM subjects, respectively. The serum concentrations of CP-122,721 reached a peak of 7.4 and 69.8 ng/ml for extensive and poor metabolizers, respectively. The major metabolic pathways of CP-122,721 were due to O-demethylation, aromatic hydroxylation, and indirect glucuronidation. The minor metabolic pathways included aliphatic oxidation at the piperidine moiety, O-dealkylation of the trifluoromethoxy group, N-dealkylation, and oxidative deamination. In addition to the major human circulating metabolite 5-trifluoromethoxy salicylic acid (TFMSA), all other circulating metabolites of CP-122,721 were glucuronide conjugates of oxidized metabolites. TFMSA was identified using high pressure liquid chromatography/tandem mass spectrometry and NMR and mechanisms were proposed for its formation. There are no known circulating active metabolites of CP-122,721.
在6名健康男性受试者（4名细胞色素P450 2D6的快代谢者和2名慢代谢者）中，口服单剂量30毫克的[14C]CP - 122,721后，对一种强效且选择性的P物质受体拮抗剂CP - 122,721 [（+）-（2S，3S）-3 - （2 - 甲氧基 - 5 - 三氟甲氧基苄基氨基）-2 - 苯基哌啶]的代谢、药代动力学及排泄情况进行了研究。在312小时内，约84%的给药放射性从受试者的尿液和粪便中回收。快代谢受试者约80%的剂量在48小时内回收。然而，慢代谢受试者在48小时内仅排泄约45%的剂量，需要完整的312小时才能实现近80%的回收。CP - 122,721在快代谢者和慢代谢者中的吸收均迅速，血清中放射性的快速出现表明了这一点。总放射性的血清浓度始终远高于未变化药物的浓度，表明代谢产物早期形成。快代谢和慢代谢受试者的CP - 122,721平均半衰期分别为6.7小时和45.0小时。CP - 122,721的血清浓度在快代谢者和慢代谢者中分别达到峰值7.4和69.8纳克/毫升。CP - 122,721的主要代谢途径是O - 去甲基化、芳香族羟基化和间接葡萄糖醛酸化。次要代谢途径包括哌啶部分的脂肪族氧化、三氟甲氧基的O - 脱烷基化、N - 脱烷基化和氧化脱氨。除了主要的人体循环代谢产物5 - 三氟甲氧基水杨酸（TFMSA）外，CP - 122,721的所有其他循环代谢产物都是氧化代谢产物的葡萄糖醛酸共轭物。TFMSA通过高压液相色谱/串联质谱和核磁共振鉴定，并提出了其形成机制。CP - 122,721没有已知的循环活性代谢产物。
