Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704
Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger approved for the treatment of amyotrophic lateral sclerosis, a fatal neuromuscular disease. Edaravone is administered as an intravenous infusion over 60 min for several treatment cycles. To ease the burden of patients and ca...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-09-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/9/1406 |
| _version_ | 1797517581680115712 |
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| author | Dong Wook Kang Ju Hee Kim Kyung Min Kim Seok-jin Cho Hee-Woon Jang Ji Won Chang Seung Myung Dong Jee Woong Lim Jae-Sun Kim Hea-Young Cho |
| author_facet | Dong Wook Kang Ju Hee Kim Kyung Min Kim Seok-jin Cho Hee-Woon Jang Ji Won Chang Seung Myung Dong Jee Woong Lim Jae-Sun Kim Hea-Young Cho |
| author_sort | Dong Wook Kang |
| collection | DOAJ |
| description | Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger approved for the treatment of amyotrophic lateral sclerosis, a fatal neuromuscular disease. Edaravone is administered as an intravenous infusion over 60 min for several treatment cycles. To ease the burden of patients and caregivers, the oral formulation of edaravone has been developed. The purpose of this study was to evaluate pharmacokinetics and tissue distribution of TEJ-1704, an edaravone oral prodrug, in male Sprague Dawley rats and beagle dogs. Animal experiments were conducted using Sprague Dawley rats and beagle dogs to evaluate pharmacokinetics, tissue distribution, and excretion of TEJ-1704. Blood, tissues, cerebrospinal fluid, urine, and feces samples were collected at designated sampling time after intravenous (IV) or oral (PO) administration of edaravone or TEJ-1704. A modified bioanalysis method was developed to quantify edaravone in samples including plasma, tissues, cerebrospinal fluid, urine, and feces. The bioanalysis method was validated and successfully applied to pharmacokinetics, tissue distribution, and excretion studies of the novel edaravone prodrug. Although plasma C<sub>max</sub> of TEJ-1704 was low, groups administered with TEJ-1704 had high AUC<sub>inf</sub>, suggesting continuous metabolism of TEJ-1704 into edaravone. Groups treated with TEJ-1704 also showed lower CSF distribution than the control groups. After the administration of TEJ-1704, the majority of edaravone was distributed to the heart, lung, and kidney. It was excreted equally via urine and feces. The pharmacokinetics, tissue distribution, and excretion of TEJ-1704, a novel edaravone oral prodrug, were successfully characterized. Additional studies are needed to fully understand the difference between TEJ-1704 and edaravone and determine the potency of TEJ-1704. |
| first_indexed | 2024-03-10T07:18:31Z |
| format | Article |
| id | doaj.art-a86deb605e67422a85de7ee80122c8e0 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T07:18:31Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-a86deb605e67422a85de7ee80122c8e02023-11-22T14:47:13ZengMDPI AGPharmaceutics1999-49232021-09-01139140610.3390/pharmaceutics13091406Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704Dong Wook Kang0Ju Hee Kim1Kyung Min Kim2Seok-jin Cho3Hee-Woon Jang4Ji Won Chang5Seung Myung Dong6Jee Woong Lim7Jae-Sun Kim8Hea-Young Cho9College of Pharmacy, CHA University, 335 Pangyo-ro, Seongnam 13488, KoreaCollege of Pharmacy, CHA University, 335 Pangyo-ro, Seongnam 13488, KoreaCollege of Pharmacy, CHA University, 335 Pangyo-ro, Seongnam 13488, KoreaCollege of Pharmacy, CHA University, 335 Pangyo-ro, Seongnam 13488, KoreaCollege of Pharmacy, CHA University, 335 Pangyo-ro, Seongnam 13488, KoreaTheragen Etex Co., Ltd., 190 Gangnam-daero, Seoul 06744, KoreaTheragen Etex Co., Ltd., 190 Gangnam-daero, Seoul 06744, KoreaJ2HBiotech Inc., 142-10 Saenam-ro, Suwon 16648, KoreaJ2HBiotech Inc., 142-10 Saenam-ro, Suwon 16648, KoreaCollege of Pharmacy, CHA University, 335 Pangyo-ro, Seongnam 13488, KoreaEdaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger approved for the treatment of amyotrophic lateral sclerosis, a fatal neuromuscular disease. Edaravone is administered as an intravenous infusion over 60 min for several treatment cycles. To ease the burden of patients and caregivers, the oral formulation of edaravone has been developed. The purpose of this study was to evaluate pharmacokinetics and tissue distribution of TEJ-1704, an edaravone oral prodrug, in male Sprague Dawley rats and beagle dogs. Animal experiments were conducted using Sprague Dawley rats and beagle dogs to evaluate pharmacokinetics, tissue distribution, and excretion of TEJ-1704. Blood, tissues, cerebrospinal fluid, urine, and feces samples were collected at designated sampling time after intravenous (IV) or oral (PO) administration of edaravone or TEJ-1704. A modified bioanalysis method was developed to quantify edaravone in samples including plasma, tissues, cerebrospinal fluid, urine, and feces. The bioanalysis method was validated and successfully applied to pharmacokinetics, tissue distribution, and excretion studies of the novel edaravone prodrug. Although plasma C<sub>max</sub> of TEJ-1704 was low, groups administered with TEJ-1704 had high AUC<sub>inf</sub>, suggesting continuous metabolism of TEJ-1704 into edaravone. Groups treated with TEJ-1704 also showed lower CSF distribution than the control groups. After the administration of TEJ-1704, the majority of edaravone was distributed to the heart, lung, and kidney. It was excreted equally via urine and feces. The pharmacokinetics, tissue distribution, and excretion of TEJ-1704, a novel edaravone oral prodrug, were successfully characterized. Additional studies are needed to fully understand the difference between TEJ-1704 and edaravone and determine the potency of TEJ-1704.https://www.mdpi.com/1999-4923/13/9/1406pharmacokineticstissue distributionexcretionedaravone oral prodrugamyotrophic lateral sclerosis |
| spellingShingle | Dong Wook Kang Ju Hee Kim Kyung Min Kim Seok-jin Cho Hee-Woon Jang Ji Won Chang Seung Myung Dong Jee Woong Lim Jae-Sun Kim Hea-Young Cho Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704 Pharmaceutics pharmacokinetics tissue distribution excretion edaravone oral prodrug amyotrophic lateral sclerosis |
| title | Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704 |
| title_full | Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704 |
| title_fullStr | Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704 |
| title_full_unstemmed | Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704 |
| title_short | Pre-Clinical Pharmacokinetic Characterization, Tissue Distribution, and Excretion Studies of Novel Edaravone Oral Prodrug, TEJ-1704 |
| title_sort | pre clinical pharmacokinetic characterization tissue distribution and excretion studies of novel edaravone oral prodrug tej 1704 |
| topic | pharmacokinetics tissue distribution excretion edaravone oral prodrug amyotrophic lateral sclerosis |
| url | https://www.mdpi.com/1999-4923/13/9/1406 |
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