In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression
Context Toddalolactone, the main component of Toddalia asiatica (L.) Lam. (Rutaceae), has anticancer, antihypertension, anti-inflammatory, and antifungal activities.Objective This study investigated the metabolic characteristics of toddalolactone.Materials and methods Toddalolactone metabolic stabil...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Pharmaceutical Biology |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/13880209.2022.2108062 |
| _version_ | 1811342501566480384 |
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| author | Lina Shan Xianbao Shi Tingting Hu Jiayin Hu Zhe Guo Yonggui Song Dan Su Xiaoyong Zhang |
| author_facet | Lina Shan Xianbao Shi Tingting Hu Jiayin Hu Zhe Guo Yonggui Song Dan Su Xiaoyong Zhang |
| author_sort | Lina Shan |
| collection | DOAJ |
| description | Context Toddalolactone, the main component of Toddalia asiatica (L.) Lam. (Rutaceae), has anticancer, antihypertension, anti-inflammatory, and antifungal activities.Objective This study investigated the metabolic characteristics of toddalolactone.Materials and methods Toddalolactone metabolic stabilities were investigated by incubating toddalolactone (20 μM) with liver microsomes from humans, rabbits, mice, rats, dogs, minipigs, and monkeys for 0, 30, 60, and 90 min. The CYP isoforms involved in toddalolactone metabolism were characterized based on chemical inhibition studies and screening assays. The effects of toddalolactone (0, 10, and 50 µM) on CYP1A1 and CYP3A5 protein expression were investigated by immunoblotting. After injecting toddalolactone (10 mg/kg), in vivo pharmacokinetic profiles using six Sprague–Dawley rats were investigated by taking 9-time points, including 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 h.Results Monkeys showed the greatest metabolic capacity in CYP-mediated and UGT-mediated reaction systems with short half-lives (T1/2) of 245 and 66 min, respectively, while T1/2 of humans in two reaction systems were 673 and 83 min, respectively. CYP1A1 and CYP3A5 were the major CYP isoforms involved in toddalolactone biotransformation. Induction of CYP1A1 protein expression by 50 μM toddalolactone was approximately 50% greater than that of the control (0 μM). Peak plasma concentration (Cmax) for toddalolactone was 0.42 μg/mL, and Tmax occurred at 0.25 h post-dosing. The elimination t1/2 was 1.05 h, and the AUC0–t was 0.46 μg/mL/h.Conclusions These findings demonstrated the significant species differences of toddalolactone metabolic profiles, which will promote appropriate species selection in further toddalolactone studies. |
| first_indexed | 2024-04-13T19:13:34Z |
| format | Article |
| id | doaj.art-3d6e093ec0994beda48894a787d9c4a5 |
| institution | Directory Open Access Journal |
| issn | 1388-0209 1744-5116 |
| language | English |
| last_indexed | 2024-04-13T19:13:34Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Pharmaceutical Biology |
| spelling | doaj.art-3d6e093ec0994beda48894a787d9c4a52022-12-22T02:33:46ZengTaylor & Francis GroupPharmaceutical Biology1388-02091744-51162022-12-016011591160510.1080/13880209.2022.2108062In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expressionLina Shan0Xianbao Shi1Tingting Hu2Jiayin Hu3Zhe Guo4Yonggui Song5Dan Su6Xiaoyong Zhang7The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, ChinaThe First Affiliated Hospital of Jinzhou Medical University, Jinzhou, ChinaThe First Affiliated Hospital of Jinzhou Medical University, Jinzhou, ChinaThe First Affiliated Hospital of Jinzhou Medical University, Jinzhou, ChinaThe First Affiliated Hospital of Jinzhou Medical University, Jinzhou, ChinaJiangxi University of Traditional Chinese Medicine, Nanchang, ChinaJiangxi University of Traditional Chinese Medicine, Nanchang, ChinaThe First Affiliated Hospital of Jinzhou Medical University, Jinzhou, ChinaContext Toddalolactone, the main component of Toddalia asiatica (L.) Lam. (Rutaceae), has anticancer, antihypertension, anti-inflammatory, and antifungal activities.Objective This study investigated the metabolic characteristics of toddalolactone.Materials and methods Toddalolactone metabolic stabilities were investigated by incubating toddalolactone (20 μM) with liver microsomes from humans, rabbits, mice, rats, dogs, minipigs, and monkeys for 0, 30, 60, and 90 min. The CYP isoforms involved in toddalolactone metabolism were characterized based on chemical inhibition studies and screening assays. The effects of toddalolactone (0, 10, and 50 µM) on CYP1A1 and CYP3A5 protein expression were investigated by immunoblotting. After injecting toddalolactone (10 mg/kg), in vivo pharmacokinetic profiles using six Sprague–Dawley rats were investigated by taking 9-time points, including 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 h.Results Monkeys showed the greatest metabolic capacity in CYP-mediated and UGT-mediated reaction systems with short half-lives (T1/2) of 245 and 66 min, respectively, while T1/2 of humans in two reaction systems were 673 and 83 min, respectively. CYP1A1 and CYP3A5 were the major CYP isoforms involved in toddalolactone biotransformation. Induction of CYP1A1 protein expression by 50 μM toddalolactone was approximately 50% greater than that of the control (0 μM). Peak plasma concentration (Cmax) for toddalolactone was 0.42 μg/mL, and Tmax occurred at 0.25 h post-dosing. The elimination t1/2 was 1.05 h, and the AUC0–t was 0.46 μg/mL/h.Conclusions These findings demonstrated the significant species differences of toddalolactone metabolic profiles, which will promote appropriate species selection in further toddalolactone studies.https://www.tandfonline.com/doi/10.1080/13880209.2022.2108062Liver microsomesspecies differenceenzyme kineticspharmacokineticsLC-MS/MS |
| spellingShingle | Lina Shan Xianbao Shi Tingting Hu Jiayin Hu Zhe Guo Yonggui Song Dan Su Xiaoyong Zhang In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression Pharmaceutical Biology Liver microsomes species difference enzyme kinetics pharmacokinetics LC-MS/MS |
| title | In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression |
| title_full | In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression |
| title_fullStr | In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression |
| title_full_unstemmed | In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression |
| title_short | In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression |
| title_sort | in vitro differences in toddalolactone metabolism in various species and its effect on cytochrome p450 expression |
| topic | Liver microsomes species difference enzyme kinetics pharmacokinetics LC-MS/MS |
| url | https://www.tandfonline.com/doi/10.1080/13880209.2022.2108062 |
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