Inhibition of P-Glycoprotein Asymmetrically Alters the In Vivo Exposure Profile of SGC003F: A Novel Guanylate Cyclase Stimulator
As a novel guanylate cyclase stimulator, SGC003F is being developed for the treatment of heart failure with a reduced ejection fraction (HFrEF). This study aimed to assess the effect of P-glycoprotein (P-gp) inhibition on SGC003F exposure in vivo, comparing plasma and tissue levels, and evaluating t...
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MDPI AG
2024-08-01
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| Online Access: | https://www.mdpi.com/1424-8247/17/9/1140 |
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| author | Jinle Lou Nan Li Xue Jiang Xu Cai Lingchao Wang Xia Wu Wenpeng Zhang Chunmei Jin Xiaomei Zhuang |
| author_facet | Jinle Lou Nan Li Xue Jiang Xu Cai Lingchao Wang Xia Wu Wenpeng Zhang Chunmei Jin Xiaomei Zhuang |
| author_sort | Jinle Lou |
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| description | As a novel guanylate cyclase stimulator, SGC003F is being developed for the treatment of heart failure with a reduced ejection fraction (HFrEF). This study aimed to assess the effect of P-glycoprotein (P-gp) inhibition on SGC003F exposure in vivo, comparing plasma and tissue levels, and evaluating the role of P-gp in the small intestine, blood–brain barrier (BBB), and kidney in impacting the tissue exposure. Tariquidar, a P-gp inhibitor, was added to monolayer transport assays to observe the changes in the transmembrane characteristics of SGC003F. Rats were given SGC003F with tariquidar via various routes to measure plasma, tissue, urine, and fecal concentrations. The inclusion of tariquidar significantly altered the pharmacokinetics of SGC003F. In LLC-PK1-MDR1 cells, tariquidar reduced the efflux ratio of SGC003F from 6.56 to 1.28. In rats, it enhanced the plasma AUC by 3.05 or 1.61 times, increased the Cmax by 2.13 or 1.07 times, and notably improved bioavailability from 46.4% to 95%. Additionally, co-administration with tariquidar led to a decrease in fecal excretion and an increase in tissue exposure, with only a moderate effect on the partition ratios in the small intestine and brain. P-gp inhibition impacts SGC003F exposure, with plasma levels not fully reflecting tissue levels. P-gp in the small intestine and BBB affects SGC003F’s pharmacokinetics, warranting further clinical drug–drug interaction (DDI) studies. |
| format | Article |
| id | doaj-art-622bc75714a74540ae40eaaf3a34df27 |
| institution | OA Journals |
| issn | 1424-8247 |
| language | English |
| publishDate | 2024-08-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj-art-622bc75714a74540ae40eaaf3a34df272025-08-20T01:55:46ZengMDPI AGPharmaceuticals1424-82472024-08-01179114010.3390/ph17091140Inhibition of P-Glycoprotein Asymmetrically Alters the In Vivo Exposure Profile of SGC003F: A Novel Guanylate Cyclase StimulatorJinle Lou0Nan Li1Xue Jiang2Xu Cai3Lingchao Wang4Xia Wu5Wenpeng Zhang6Chunmei Jin7Xiaomei Zhuang8Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaCollege of Pharmay, Yanbian University, Yanji 133000, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaAs a novel guanylate cyclase stimulator, SGC003F is being developed for the treatment of heart failure with a reduced ejection fraction (HFrEF). This study aimed to assess the effect of P-glycoprotein (P-gp) inhibition on SGC003F exposure in vivo, comparing plasma and tissue levels, and evaluating the role of P-gp in the small intestine, blood–brain barrier (BBB), and kidney in impacting the tissue exposure. Tariquidar, a P-gp inhibitor, was added to monolayer transport assays to observe the changes in the transmembrane characteristics of SGC003F. Rats were given SGC003F with tariquidar via various routes to measure plasma, tissue, urine, and fecal concentrations. The inclusion of tariquidar significantly altered the pharmacokinetics of SGC003F. In LLC-PK1-MDR1 cells, tariquidar reduced the efflux ratio of SGC003F from 6.56 to 1.28. In rats, it enhanced the plasma AUC by 3.05 or 1.61 times, increased the Cmax by 2.13 or 1.07 times, and notably improved bioavailability from 46.4% to 95%. Additionally, co-administration with tariquidar led to a decrease in fecal excretion and an increase in tissue exposure, with only a moderate effect on the partition ratios in the small intestine and brain. P-gp inhibition impacts SGC003F exposure, with plasma levels not fully reflecting tissue levels. P-gp in the small intestine and BBB affects SGC003F’s pharmacokinetics, warranting further clinical drug–drug interaction (DDI) studies.https://www.mdpi.com/1424-8247/17/9/1140SGC003FP-gpdrug–drug interactionstissue distributionexcretion |
| spellingShingle | Jinle Lou Nan Li Xue Jiang Xu Cai Lingchao Wang Xia Wu Wenpeng Zhang Chunmei Jin Xiaomei Zhuang Inhibition of P-Glycoprotein Asymmetrically Alters the In Vivo Exposure Profile of SGC003F: A Novel Guanylate Cyclase Stimulator Pharmaceuticals SGC003F P-gp drug–drug interactions tissue distribution excretion |
| title | Inhibition of P-Glycoprotein Asymmetrically Alters the In Vivo Exposure Profile of SGC003F: A Novel Guanylate Cyclase Stimulator |
| title_full | Inhibition of P-Glycoprotein Asymmetrically Alters the In Vivo Exposure Profile of SGC003F: A Novel Guanylate Cyclase Stimulator |
| title_fullStr | Inhibition of P-Glycoprotein Asymmetrically Alters the In Vivo Exposure Profile of SGC003F: A Novel Guanylate Cyclase Stimulator |
| title_full_unstemmed | Inhibition of P-Glycoprotein Asymmetrically Alters the In Vivo Exposure Profile of SGC003F: A Novel Guanylate Cyclase Stimulator |
| title_short | Inhibition of P-Glycoprotein Asymmetrically Alters the In Vivo Exposure Profile of SGC003F: A Novel Guanylate Cyclase Stimulator |
| title_sort | inhibition of p glycoprotein asymmetrically alters the in vivo exposure profile of sgc003f a novel guanylate cyclase stimulator |
| topic | SGC003F P-gp drug–drug interactions tissue distribution excretion |
| url | https://www.mdpi.com/1424-8247/17/9/1140 |
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