Investigation of the pharmacokinetics and metabolic fate of Fasiglifam (TAK-875) in male and female rats following oral and intravenous administration
The metabolism and pharmacokinetics of fasiglifam (TAK-875, 2-[(3S)-6-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid), a selective free fatty acid receptor 1 (FFAR1)/GPR40 agonist, were studied following intravenous (5 mg/kg) and oral administration (10 and 50 mg/kg) to male and female Sprague Dawley rats.Following intravenous dosing at 5 mg/kg, peak observed plasma concentrations of 8.8/9.2 µg/ml were seen in male and female rats respectively.Following oral dosing, peak plasma concentrations at 1 h of ca. 12.4/12.9 µg/ml for 10 mg/kg and 76.2/83.7 µg/ml for 50 mg/kg doses were obtained for male and female rats respectively. Drug concentrations then declined in the plasma of both sexes with t1/2's of 12.4 (male) and 11.2 h (female). Oral bioavailability was estimated to be 85-120% in males and females at both dose levels.Urinary excretion was low, but in a significant sex-related difference, female rats eliminated ca. 10-fold more drug-related material by this route.Fasiglifam was the principal drug-related compound in plasma, with 15 metabolites, including the acyl glucuronide, also detected. In addition to previously identified metabolites, a novel biotransformation, that produced a side-chain shortened metabolite via elimination of CH2 from the acetyl side chain was noted with implications for drug toxicity.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:53 |
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| Enthalten in: |
Xenobiotica; the fate of foreign compounds in biological systems - 53(2023), 2 vom: 01. Feb., Seite 93-105 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Molloy, Billy J [VerfasserIn] |
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| Links: |
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| Themen: |
Fasiglifam |
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| Anmerkungen: |
Date Completed 10.05.2023 Date Revised 10.05.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1080/00498254.2023.2179952 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM35301088X |
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| 100 | 1 | |a Molloy, Billy J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Investigation of the pharmacokinetics and metabolic fate of Fasiglifam (TAK-875) in male and female rats following oral and intravenous administration |
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| 500 | |a Date Revised 10.05.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The metabolism and pharmacokinetics of fasiglifam (TAK-875, 2-[(3S)-6-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid), a selective free fatty acid receptor 1 (FFAR1)/GPR40 agonist, were studied following intravenous (5 mg/kg) and oral administration (10 and 50 mg/kg) to male and female Sprague Dawley rats.Following intravenous dosing at 5 mg/kg, peak observed plasma concentrations of 8.8/9.2 µg/ml were seen in male and female rats respectively.Following oral dosing, peak plasma concentrations at 1 h of ca. 12.4/12.9 µg/ml for 10 mg/kg and 76.2/83.7 µg/ml for 50 mg/kg doses were obtained for male and female rats respectively. Drug concentrations then declined in the plasma of both sexes with t1/2's of 12.4 (male) and 11.2 h (female). Oral bioavailability was estimated to be 85-120% in males and females at both dose levels.Urinary excretion was low, but in a significant sex-related difference, female rats eliminated ca. 10-fold more drug-related material by this route.Fasiglifam was the principal drug-related compound in plasma, with 15 metabolites, including the acyl glucuronide, also detected. In addition to previously identified metabolites, a novel biotransformation, that produced a side-chain shortened metabolite via elimination of CH2 from the acetyl side chain was noted with implications for drug toxicity | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Fasiglifam | |
| 650 | 4 | |a metabolite profiling | |
| 650 | 4 | |a novel metabolites | |
| 650 | 4 | |a oxidative decarboxylaton | |
| 650 | 4 | |a pharmacokinetics | |
| 650 | 4 | |a sex differences | |
| 650 | 7 | |a TAK-875 |2 NLM | |
| 650 | 7 | |a Sulfones |2 NLM | |
| 650 | 7 | |a Receptors, G-Protein-Coupled |2 NLM | |
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| 700 | 1 | |a Gethings, Lee A |e verfasserin |4 aut | |
| 700 | 1 | |a Plumb, Robert S |e verfasserin |4 aut | |
| 700 | 1 | |a Mortishire-Smith, Russell J |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Ian D |e verfasserin |4 aut | |
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