Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in Rats
Supinoxin is a novel anticancer drug candidate targeting the Y593 phospho-p68 RNA helicase, by exhibiting antiproliferative activity and/or suppression of tumor growth. This study aimed to characterize the in vitro and in vivo pharmacokinetics of supinoxin and attempt physiologically based pharmacok...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-03-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/3/373 |
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| author | Yoo-Kyung Song Yun-Hwan Seol Min Ju Kim Jong-Woo Jeong Hae-In Choi Seung-Won Lee Yoon-Jee Chae Sunjoo Ahn Young-Dae Gong Kyeong-Ryoon Lee Tae-Sung Koo |
| author_facet | Yoo-Kyung Song Yun-Hwan Seol Min Ju Kim Jong-Woo Jeong Hae-In Choi Seung-Won Lee Yoon-Jee Chae Sunjoo Ahn Young-Dae Gong Kyeong-Ryoon Lee Tae-Sung Koo |
| author_sort | Yoo-Kyung Song |
| collection | DOAJ |
| description | Supinoxin is a novel anticancer drug candidate targeting the Y593 phospho-p68 RNA helicase, by exhibiting antiproliferative activity and/or suppression of tumor growth. This study aimed to characterize the in vitro and in vivo pharmacokinetics of supinoxin and attempt physiologically based pharmacokinetic (PBPK) modeling in rats. Supinoxin has good permeability, comparable to that of metoprolol (high permeability compound) in Caco-2 cells, with negligible net absorptive or secretory transport observed. After an intravenous injection at a dose range of 0.5–5 mg/kg, the terminal half-life (i.e., 2.54–2.80 h), systemic clearance (i.e., 691–865 mL/h/kg), and steady state volume of distribution (i.e., 2040–3500 mL/kg) of supinoxin remained unchanged, suggesting dose-independent (i.e., dose-proportional) pharmacokinetics for the dose ranges studied. After oral administration, supinoxin showed modest absorption with an absolute oral bioavailability of 56.9–57.4%. The fecal recovery following intravenous and oral administration was 16.5% and 46.8%, respectively, whereas the urinary recoveries in both administration routes were negligible. Supinoxin was mainly eliminated via NADPH-dependent phase I metabolism (i.e., 58.5% of total clearance), while UDPGA-dependent phase II metabolism appeared negligible in the rat liver microsome. Supinoxin was most abundantly distributed in the adipose tissue, gut, and liver among the nine major tissues studied (i.e., the brain, liver, kidneys, heart, lungs, spleen, gut, muscles, and adipose tissue), and the tissue exposure profiles of supinoxin were well predicted with physiologically based pharmacokinetics. |
| first_indexed | 2024-03-10T13:19:45Z |
| format | Article |
| id | doaj.art-dcd06b6dbdef4d99bf9cab27fa2aa6dd |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T13:19:45Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-dcd06b6dbdef4d99bf9cab27fa2aa6dd2023-11-21T10:09:19ZengMDPI AGPharmaceutics1999-49232021-03-0113337310.3390/pharmaceutics13030373Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in RatsYoo-Kyung Song0Yun-Hwan Seol1Min Ju Kim2Jong-Woo Jeong3Hae-In Choi4Seung-Won Lee5Yoon-Jee Chae6Sunjoo Ahn7Young-Dae Gong8Kyeong-Ryoon Lee9Tae-Sung Koo10Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup 28116, KoreaGraduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, KoreaLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup 28116, KoreaLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup 28116, KoreaGraduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, KoreaGraduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, KoreaCollege of Pharmacy, Woosuk University, Wanju-Gun 55338, KoreaTherapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, KoreaInnovative Drug Library Research Center, Department of Chemistry, College of Science, Dongguk University, Seoul 04620, KoreaLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup 28116, KoreaGraduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, KoreaSupinoxin is a novel anticancer drug candidate targeting the Y593 phospho-p68 RNA helicase, by exhibiting antiproliferative activity and/or suppression of tumor growth. This study aimed to characterize the in vitro and in vivo pharmacokinetics of supinoxin and attempt physiologically based pharmacokinetic (PBPK) modeling in rats. Supinoxin has good permeability, comparable to that of metoprolol (high permeability compound) in Caco-2 cells, with negligible net absorptive or secretory transport observed. After an intravenous injection at a dose range of 0.5–5 mg/kg, the terminal half-life (i.e., 2.54–2.80 h), systemic clearance (i.e., 691–865 mL/h/kg), and steady state volume of distribution (i.e., 2040–3500 mL/kg) of supinoxin remained unchanged, suggesting dose-independent (i.e., dose-proportional) pharmacokinetics for the dose ranges studied. After oral administration, supinoxin showed modest absorption with an absolute oral bioavailability of 56.9–57.4%. The fecal recovery following intravenous and oral administration was 16.5% and 46.8%, respectively, whereas the urinary recoveries in both administration routes were negligible. Supinoxin was mainly eliminated via NADPH-dependent phase I metabolism (i.e., 58.5% of total clearance), while UDPGA-dependent phase II metabolism appeared negligible in the rat liver microsome. Supinoxin was most abundantly distributed in the adipose tissue, gut, and liver among the nine major tissues studied (i.e., the brain, liver, kidneys, heart, lungs, spleen, gut, muscles, and adipose tissue), and the tissue exposure profiles of supinoxin were well predicted with physiologically based pharmacokinetics.https://www.mdpi.com/1999-4923/13/3/373phosphorylated p68supinoxinpharmacokineticsphysiologically based pharmacokinetic modeling |
| spellingShingle | Yoo-Kyung Song Yun-Hwan Seol Min Ju Kim Jong-Woo Jeong Hae-In Choi Seung-Won Lee Yoon-Jee Chae Sunjoo Ahn Young-Dae Gong Kyeong-Ryoon Lee Tae-Sung Koo Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in Rats Pharmaceutics phosphorylated p68 supinoxin pharmacokinetics physiologically based pharmacokinetic modeling |
| title | Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in Rats |
| title_full | Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in Rats |
| title_fullStr | Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in Rats |
| title_full_unstemmed | Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in Rats |
| title_short | Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in Rats |
| title_sort | pharmacokinetic characterization of supinoxin and its physiologically based pharmacokinetic modeling in rats |
| topic | phosphorylated p68 supinoxin pharmacokinetics physiologically based pharmacokinetic modeling |
| url | https://www.mdpi.com/1999-4923/13/3/373 |
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