Wang Amy Q, Hagen Natalie R, Padilha Elias C, Yang Mengbi, Shah Pranav, Chen Catherine Z, Huang Wenwei, Terse Pramod, Sanderson Philip, Zheng Wei, Xu Xin
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, United States.
Front Pharmacol. 2022 Aug 16;13:918083. doi: 10.3389/fphar.2022.918083. eCollection 2022.
Preclinical pharmacokinetics (PK) and ADME properties of GS-441524, a potential oral agent for the treatment of Covid-19, were studied. GS-441524 was stable in liver microsomes, cytosols, and hepatocytes of mice, rats, monkeys, dogs, and humans. The plasma free fractions of GS-441524 were 62-78% across all studied species. The transporter study results showed that GS-441524 was a substrate of MDR1, BCRP, CNT3, ENT1, and ENT2; but not a substrate of CNT1, CNT2, and ENT4. GS-441524 had a low to moderate plasma clearance (CL), ranging from 4.1 mL/min/kg in dogs to 26 mL/min/kg in mice; the steady state volume distribution (Vd) ranged from 0.9 L/kg in dogs to 2.4 L/kg in mice after IV administration. Urinary excretion appeared to be the major elimination process for GS-441524. Following oral administration, the oral bioavailability was 8.3% in monkeys, 33% in rats, 39% in mice, and 85% in dogs. The PK and ADME properties of GS-441524 support its further development as an oral drug candidate.
对GS-441524（一种潜在的用于治疗新冠肺炎的口服药物）的临床前药代动力学（PK）和药物代谢动力学（ADME）特性进行了研究。GS-441524在小鼠、大鼠、猴子、狗和人类的肝微粒体、胞质溶胶和肝细胞中均稳定。在所有研究物种中，GS-441524的血浆游离分数为62%-78%。转运体研究结果表明，GS-441524是多药耐药蛋白1（MDR1）、乳腺癌耐药蛋白（BCRP）、钠-协同转运蛋白3（CNT3）、等效核苷转运体1（ENT1）和等效核苷转运体2（ENT2）的底物；但不是钠-协同转运蛋白1（CNT1）、钠-协同转运蛋白2（CNT2）和等效核苷转运体4（ENT4）的底物。GS-441524的血浆清除率（CL）低至中等，静脉注射后，犬的血浆清除率为4.1 mL/（min·kg），小鼠为26 mL/（min·kg）；稳态分布容积（Vd）范围为犬0.9 L/kg，小鼠2.4 L/kg。尿液排泄似乎是GS-441524的主要消除过程。口服给药后，GS-441524在猴子中的口服生物利用度为8.3%，大鼠为33%，小鼠为39%，狗为85%。GS-441524的PK和ADME特性支持其作为口服候选药物的进一步开发。
