Differential inhibition of sildenafil and macitentan on saxagliptin metabolism

作者全名：Dai, Ge-xin; Tan, Wei; Shen, Yuxin; Lin, Dongdong; Xu, Ren-ai; Lin, Qianmeng; Wei, Zhen

作者地址：[Dai, Ge-xin; Shen, Yuxin; Xu, Ren-ai; Wei, Zhen] Wenzhou Med Univ, Affiliated Hosp 1, Wenzhou 325035, Zhejiang, Peoples R China; [Tan, Wei] Chongqing Med Univ, Affiliated Hosp 3, Gener Hosp, Chongqing 401120, Peoples R China; [Lin, Dongdong] Wenzhou Med Univ, Sch Pharmaceut Sci, Wenzhou 325035, Zhejiang, Peoples R China; [Lin, Qianmeng] Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Dept Oncol,Dept Pathol,NHC Key Lab Canc Prote, Changsha 410008, Hunan, Peoples R China; [Lin, Qianmeng] Cent South Univ, Xiangya Hosp, State Local Joint Engn Lab Anticanc Drugs, Changsha 410008, Hunan, Peoples R China

通信作者：Wei, Z (通讯作者)，Wenzhou Med Univ, Affiliated Hosp 1, Wenzhou 325035, Zhejiang, Peoples R China.; Lin, QM (通讯作者)，Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Dept Oncol,Dept Pathol,NHC Key Lab Canc Prote, Changsha 410008, Hunan, Peoples R China.; Lin, QM (通讯作者)，Cent South Univ, Xiangya Hosp, State Local Joint Engn Lab Anticanc Drugs, Changsha 410008, Hunan, Peoples R China.

来源：TOXICOLOGY AND APPLIED PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001235936800001

JCR分区：Q2

影响因子：3.3

年份：2024

卷号：486

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Editor: Lawrence Lash; Saxagliptin; Sildenafil; Macitentan; Drug-Drug Interaction; Molecular Docking

摘要：The development of diabetes mellitus (DM) is generally accompanied by erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), which increases the use of combination drug therapy and the risk of drug-drug interactions. Saxagliptin for the treatment of DM, sildenafil for the treatment of ED and PAH, and macitentan for the treatment of PAH are all substrates of CYP3A4, which indicates their potential involvement in drug-drug interactions. Therefore, we investigated potential pharmacokinetic interactions between saxagliptin and sildenafil/macitentan. We investigated this speculation both in vitro and in vivo, and explored the underlying mechanism using in vitro hepatic metabolic models and molecular docking assays. The results showed that sildenafil substantially inhibited the metabolism of saxagliptin by occupying the catalytic site of CYP3A4 in a competitive manner, leading to the alterations in the pharmacokinetic properties of saxagliptin in terms of increased maximum plasma concentration (C-max), area under the plasma concentration-time curve from time 0 to 24 h (AUC((0-t))), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC((0-infinity))), decreased clearance rate (CLz/F), and prolonged terminal half-life (t(1/2)). In contrast, a slight inhibition was observed in saxagliptin metabolism when concomitantly used with macitentan, as no pharmacokinetic parameters were altered, except for CLz/F. Thus, dosage adjustment of saxagliptin may be required in combination with sildenafil to achieve safe therapeutic plasma concentrations and reduce the risk of potential toxicity, but it is not necessary for co-administration with macitentan.

基金机构：Wenzhou City Science and Tech- nology Bureau [Y20211021]; Zhejiang Pharmaceutical Association Project [2019ZYY04]

基金资助正文：This study was supported by the Wenzhou City Science and Tech- nology Bureau (Y20211021) and Zhejiang Pharmaceutical Association Project (Grant No. 2019ZYY04) .