Abstract

1. MGV354 was being developed as a novel ocular therapy for lowering of intraocular pressure, a key modifiable risk factor for glaucoma. MGV354 is an activator of soluble guanylate cyclase, an enzyme known to be involved in the regulation of IOP. MGV354 has been shown to robustly lower IOP over 24 h after a single topical ocular drop in rabbit and monkey pharmacology models. However, MGV354 failed to produce similar results in patients with ocular hypertension or open-angle glaucoma.

2. With an objective of explaining the lack of efficacy in the clinic, we attempted to study whether human metabolism was significantly different from animal metabolism. The present study documents the investigation of metabolism of MGV354 in an effort to understand potential differences in biotransformation pathways of MGV354 in rabbits, monkeys, and humans.

3. Overall twenty-six metabolites, formed via oxidative and conjugative pathways, were identified in vitro and in vivo. In vitro hepatic metabolism was qualitatively similar across species, with minor but distinct differences. There were no observable interspecies differences in the hepatic and ocular metabolism of MGV354. Although ocular metabolism was not as extensive as hepatic, the results do not explain the lack of efficacy of MGV354 in clinical studies.

摘要

1. MGV354被开发为一种新型的眼药，用于降低眼内压，这是一种可调节的青光眼危险因素。MGV354是可溶性鸟苷酸环化酶的活化剂，可溶性鸟苷酸环化酶是一种已知参与IOP调节的酶。在兔和猴的药理模型中，单次局部滴眼后，MGV354可在24小时内显着降低IOP。但是，MGV354无法在高眼压或开角型青光眼患者中产生相似的结果。

2. 为了解释临床上缺乏功效，我们尝试研究人的新陈代谢与动物新陈代谢是否有显着差异。本研究记录了MGV354代谢的研究，以了解MGV354在兔，猴子和人类中生物转化途径的潜在差异。

3. 在体外和体内鉴定了通过氧化和结合途径形成的总共二十六个代谢产物。不同物种的体外肝代谢在质量上相似，差异很小但明显。MGV354的肝和眼代谢没有明显的种间差异。尽管眼部代谢不如肝组织广泛，但该结果不能解释MGV354在临床研究中缺乏疗效。