Allen Annette E, Martin Elizabeth A, Greenwood Katherine, Grant Claire, Vince Peter, Lucas Robert J, Redfern William S
Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Regulatory Safety Centre of Excellence, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Br J Pharmacol. 2020 Oct;177(20):4734-4749. doi: 10.1111/bph.15239. Epub 2020 Sep 13.
Inhibition of monocarboxylate transport 1 (MCT1) is of interest in targeting highly glycolytic tumours. However, MCT1 is expressed in retina, and so inhibition of MCT1 could affect retinal function.
AZD3965, an MCT1 inhibitor selected for clinical development, and two additional MCT1 inhibitors were evaluated for effects on visual acuity in albino (Han Wistar) rats. The effects of AZD3965 on visual acuity and electroretinography (ERG) were further investigated in pigmented (Long-Evans) rats, with dosing for up to 7 days.
All three MCT1 inhibitors reduced visual acuity within 2 h of dosing, suggesting a class effect. The deficit caused by AZD3965 (1,000 mg·kg p.o. per day for 4 days) in Long Evans rats recovered to pre-dose levels 7 days after cessation of dosing. AZD3965 (50 to 1,000 mg·kg p.o.) reduced the amplitude of scotopic a- and b-waves, and photopic b-wave of the ERG in a dose-related fashion, within 2 h of dosing. The effects on the scotopic ERG had diminished by Day 7 of dosing, demonstrating partial restoration of function despite continued treatment. Seven days after cessation of dosing at the highest dose tested (1,000 mg·kg ), there was recovery of both scotopic a- and b- waves and, to a lesser extent, photopic b-wave. ERG was affected at lower plasma exposures than was visual function.
This study clarifies the role of the MCT1 transporter in retinal function. The monitorability of the functional effects on the retina enabled safe clinical use of AZD3965.
抑制单羧酸转运体1（MCT1）是针对高糖酵解肿瘤的一个研究方向。然而，MCT1在视网膜中表达，因此抑制MCT1可能会影响视网膜功能。
选用已进入临床开发阶段的MCT1抑制剂AZD3965以及另外两种MCT1抑制剂，评估它们对白化（Han Wistar）大鼠视力的影响。在有色（Long-Evans）大鼠中进一步研究AZD3965对视力和视网膜电图（ERG）的影响，给药长达7天。
所有三种MCT1抑制剂在给药后2小时内均降低了视力，提示存在类效应。Long Evans大鼠经AZD3965（每天口服1000 mg·kg，持续4天）给药后导致的视力缺陷在停药7天后恢复到给药前水平。AZD3965（口服50至1000 mg·kg）在给药后2小时内以剂量相关的方式降低了ERG的暗视a波和b波及明视b波的振幅。给药第7天时，对暗视ERG的影响有所减弱，表明尽管持续治疗，但功能有部分恢复。在测试的最高剂量（1000 mg·kg）停药7天后，暗视a波和b波以及程度较轻的明视b波均恢复。ERG受影响时的血浆暴露水平低于视觉功能受影响时的水平。
本研究阐明了MCT1转运体在视网膜功能中的作用。对视网膜功能影响的可监测性使得AZD3965能够安全地用于临床。
