In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity
In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity
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DOI：
10.1124/dmd.116.070672
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发表时间：
2016-10-01
影响因子：
3.9
通讯作者：
Chien, Caly
中科院分区：
文献类型：
--
作者：
Monbaliu, Johan;Gonzalez, Martha;Chien, Caly
醋酸阿比特龙是细胞色素P450 C17抑制剂阿比特龙的前药，加强的松被批准用于治疗转移性去势抵抗性前列腺癌。我们探讨了阿比特龙是否与CYP2C8代谢的药物相互作用，CYP2C8是一种负责许多药物代谢的酶。醋酸阿比特龙、阿比特龙及其主要代谢物硫酸阿比特龙和硫酸n-氧化物阿比特龙抑制人肝微粒体CYP2C8， IC50值接近或低于转移性去势抵抗前列腺癌患者的峰值总浓度（IC50值分别为1.3 ~ 3.0 μ M、1.6 ~ 2.9 μ M、0.044 ~ 0.15 μ M、5.4 ~ 5.9 μ M）。CYP2C8抑制是可逆的，且与时间无关。为了探讨体外数据的临床相关性，进行了一项开放标签的单中心研究，包括16名健康男性受试者，他们在第1天接受单次15mg剂量的CYP2C8底物吡格列酮，并在第8天给予醋酸阿比特龙1000mg后1小时再次接受吡格列酮治疗。在每次给药后72小时内测定吡格列酮、其活性M-III（酮衍生物）和M-IV（羟基衍生物）代谢物以及阿比特龙的血浆浓度。醋酸阿比特龙暴露于吡格列酮增加；几何平均比值（第8天/第1天）C-max为125[90%置信区间（CI）， 99.9-156]， AUC为146 (90% CI, 126-171)（最后）。M-III和M-IV的暴露减少了10%至13%。血浆阿比特龙浓度与先前的研究一致。这些结果表明阿比特龙在体内仅微弱抑制CYP2C8。
Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1.3-3.0 mu M, 1.6-2.9 mu M, 0.044-0.15 mu M, and 5.4-5.9 mu M, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9-156] for C-max and 146 (90% CI, 126-171) for AUC(last). Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma abiraterone concentrations were consistent with previous studies. These results show that abiraterone only weakly inhibits CYP2C8 in vivo.