{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T15:50:39Z","timestamp":1768751439375,"version":"3.49.0"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T00:00:00Z","timestamp":1724889600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2605000"],"award-info":[{"award-number":["2023YFC2605000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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\u2013brain 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\u2019s pharmacokinetics, warranting further clinical drug\u2013drug interaction (DDI) studies.<\/jats:p>","DOI":"10.3390\/ph17091140","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T08:01:47Z","timestamp":1724918507000},"page":"1140","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Inhibition of P-Glycoprotein Asymmetrically Alters the In Vivo Exposure Profile of SGC003F: A Novel Guanylate Cyclase Stimulator"],"prefix":"10.3390","volume":"17","author":[{"given":"Jinle","family":"Lou","sequence":"first","affiliation":[{"name":"Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"},{"name":"College of Pharmay, Yanbian University, Yanji 133000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"},{"name":"College of Pharmay, Yanbian University, Yanji 133000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Jiang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Cai","sequence":"additional","affiliation":[{"name":"Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingchao","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Wu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenpeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunmei","family":"Jin","sequence":"additional","affiliation":[{"name":"College of Pharmay, Yanbian University, Yanji 133000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaomei","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Xie, C., Zhang, Y., Zhu, B., Yang, L., Ren, J., and Lang, N. 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