Metabolism is hepatic by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via ß-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug to form dihydrodiols, which are further conjugated with glucuronic acid.
The metabolism and disposition of calcimimetic agent cinacalcet HCl was examined after a single oral administration to mice, rats, monkeys, and human volunteers. ... The primary routes of metabolism of cinacalcet were N-dealkylation leading to carboxylic acid derivatives (excreted in urine as glycine conjugates) and oxidation of naphthalene ring to form dihydrodiols (excreted in urine and bile as glucuronide conjugates). The plasma radioactivity in both animals and humans was primarily composed of carboxylic acid metabolites and dihydrodiol glucuronides, with <1% circulating radioactivity accounting for the unchanged cinacalcet. Overall, the circulating and excreted metabolite profile of cinacalcet in humans was qualitatively similar to that observed in preclinical animal models.
Cinacalcet is metabolized by multiple cytochrome P-450 (CYP) isoenzymes, mainly CYP3A4, CYP2D6, and CYP1A2, and is a potent inhibitor of CYP2D6 in vitro.
Rapidly and extensively metabolized hepatically by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2 via oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid which are further metabolized via beta-oxidation and glycine conjugations; the oxidative N-dealkylation process also generates metabolites that contains the naphthalene ring; and oxidation of the naphthalene ring on the parent drug to form dihydrodiols which are further conjugated with glucuronic aicd. The hydrocinnamic acid metabolite was shown to be inactive at concentrations up to 10 uM in a cell-based assay measuring calcium-receptor activation. The glucuronide conjugates formed after oxidation were shown to have a potency approximately 0.003 times that of cinacalcet in a cell-based assay measuring a calcimimetic response.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
Potential pharmacokinetic interaction (increased plasma concentrations of drugs metabolized principally by cytochrome P450 (CYP) isoenzyme 2D6). In patients receiving cinacalcet 25 or 100 mg concurrently with amitriptyline hydrochloride 50 mg, exposure to amitriptyline and its active metabolite, norrtiptyline, was increased by 20%. Dosage adjustment maybe required if cinacalcet is administered concomitantly with ta drug that has a narrow therapeutic index and is metabolized principally by CYP2D6 (e.g., flecainide, vinblastine, thioridazine, most tricyclic antidepressants).
Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6 and CYP1A2. Renal excretion of metabolites was the primary route of elimination of radioactivity.
The metabolism and disposition of calcimimetic agent cinacalcet HCl was examined after a single oral administration to mice, rats, monkeys, and human volunteers. In all species examined, cinacalcet was well absorbed, with greater than 74% oral bioavailability of cinacalcet-derived radioactivity in monkeys and humans. In rats, cinacalcet-derived radioactivity was widely distributed into most tissues, with no marked gender-related differences. In all animal models examined, radioactivity was excreted rapidly via both hepatobiliary and urinary routes. In humans, radioactivity was cleared primarily via the urinary route (80%), with 17% excreted in the feces. Cinacalcet was not detected in the urine in humans. ...
After absorption, cinacalcet concentrations decline in a biphasic fashion with a terminal half life of 30 to 40 hours. Renal excretion of metabolites was the primary route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the feces.
