Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ 08543, USA.
Drug Metab Dispos. 2012 Dec;40(12):2374-80. doi: 10.1124/dmd.112.047340. Epub 2012 Sep 14.
Brivanib alaninate is an orally administered alanine prodrug of brivanib, a dual inhibitor of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways. It is currently in clinical trials for the treatment of hepatocellular carcinoma and colorectal cancer. Brivanib has a single asymmetric center derived from a secondary alcohol. The potential for chiral inversion was investigated in incubations with liver subcellular fractions and in animals and humans after oral doses of brivanib alaninate. Incubations of [¹⁴C]brivanib alaninate with liver microsomes and cytosols from rats, monkeys, and humans followed by chiral chromatography resulted in two radioactive peaks, corresponding to brivanib and its enantiomer. The percentage of the enantiomeric metabolite relative to brivanib in microsomal and cytosolic incubations of different species in the presence of NADPH ranged from 11.6 to 15.8 and 0.8 to 3.1%, respectively. The proposed mechanism of inversion involves the oxidation of brivanib to a ketone metabolite, which is subsequently reduced to brivanib and its enantiomer. After oral doses of brivanib alaninate to rats and monkeys, the enantiomeric metabolite was a prominent drug-related component in plasma, with the percentages of area under the curve (AUC) at 94.7 and 39.7%, respectively, relative to brivanib. In humans, the enantiomeric metabolite was a minor circulating component, with the AUC <3% of brivanib. Pharmacological studies indicated that brivanib and its enantiomer had similar potency toward the inhibition of VEGF receptor-2 and FGF receptor-1 kinases. Because of low plasma concentration in humans, the enantiomeric metabolite was not expected to contribute significantly to target-related pharmacology of brivanib. Moreover, adequate exposure in the toxicology species suggested no specific safety concerns with respect to exposure to the enantiomeric metabolite.
布立尼布丙氨酸是布立尼布的一种口服丙氨酸前药，布立尼布是血管内皮生长因子（VEGF）和成纤维细胞生长因子（FGF）信号通路的双重抑制剂。它目前正在临床试验中用于治疗肝细胞癌和结直肠癌。布立尼布有一个单一的不对称中心，来源于仲醇。在肝亚细胞部分孵育以及动物和人体口服布立尼布丙氨酸后，研究了手性反转的可能性。用大鼠、猴子和人类的肝微粒体和胞质进行[¹⁴C]布立尼布丙氨酸孵育，然后进行手性色谱分析，得到两个放射性峰，分别对应布立尼布及其对映异构体。在有 NADPH 的情况下，不同物种的微粒体和胞质孵育中，对映体代谢物相对于布立尼布的百分比范围分别为 11.6%至 15.8%和 0.8%至 3.1%。反转的推测机制涉及布立尼布氧化为酮代谢物，随后还原为布立尼布及其对映异构体。在给大鼠和猴子口服布立尼布丙氨酸后，对映体代谢物是血浆中主要的药物相关成分，相对于布立尼布的 AUC 百分比分别为 94.7%和 39.7%。在人类中，对映体代谢物是一种次要的循环成分，AUC 小于布立尼布的 3%。药理学研究表明，布立尼布及其对映异构体对 VEGF 受体-2 和 FGF 受体-1 激酶的抑制作用具有相似的效力。由于在人体中的血浆浓度较低，预计对映体代谢物不会对布立尼布的靶相关药理学产生重大影响。此外，在毒理学物种中充分暴露表明，与暴露于对映体代谢物相关，没有特定的安全性问题。
