Influence of verapamil on the pharmacokinetics of rotundic acid in rats and its potential mechanism
Context Rotundic acid (RA), a plant-derived pentacyclic triterpene acid, has been reported to possess extensive pharmacological activities. The poor bioavailability limits its further development and potential clinic application. Objective To clarify the potential mechanism for poor oral bioavailabi...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2021-01-01
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| Series: | Pharmaceutical Biology |
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| Online Access: | http://dx.doi.org/10.1080/13880209.2021.1871634 |
| _version_ | 1818846586263830528 |
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| author | Haihua Shang Ze Wang Hong Ma Yinghui Sun Xiaoyan Ci Yuan Gu Changxiao Liu Duanyun Si |
| author_facet | Haihua Shang Ze Wang Hong Ma Yinghui Sun Xiaoyan Ci Yuan Gu Changxiao Liu Duanyun Si |
| author_sort | Haihua Shang |
| collection | DOAJ |
| description | Context Rotundic acid (RA), a plant-derived pentacyclic triterpene acid, has been reported to possess extensive pharmacological activities. The poor bioavailability limits its further development and potential clinic application. Objective To clarify the potential mechanism for poor oral bioavailability. Materials and methods The single-dose pharmacokinetics of orally administered RA (10 mg/kg) in Sprague–Dawley rats without or with verapamil (25 or 50 mg/kg) were investigated. Additionally, MDCKII-MDR1 and Caco-2 cell monolayers, five recombinant human cytochrome P450 (rhCYP) enzymes (1A2, 2C8, 2C9, 2D6 and 3A4), and rat liver microsomes were also conducted to investigate its potential mechanism. Results Verapamil could significantly affect the plasma concentration of RA. Co-administered verapamil at 25 and 50 mg/kg, the AUC0–∞ increased from 432 ± 64.2 to 539 ± 53.6 and 836 ± 116 ng × h/mL, respectively, and the oral clearance decreased from 23.6 ± 3.50 to 18.7 ± 1.85 and 12.2 ± 1.85 L/h/kg, respectively. The MDCKII-MDR1 cell assay showed that RA might be a P-gp substrate. The rhCYPs experiments indicated that RA was mainly metabolized by CYP3A4. Additionally, verapamil could increase the absorption of RA by inhibiting the activity of P-gp, and slow down the intrinsic clearance of RA from 48.5 ± 3.18 to 12.0 ± 1.06 µL/min/mg protein. Discussion and conclusions These findings indicated that verapamil could significantly affect the pharmacokinetic profiles of RA in rats. It was demonstrated that P-gp and CYP3A were involved in the transport and metabolism of RA, which might contribute to the low oral bioavailability of RA. |
| first_indexed | 2024-12-19T05:47:54Z |
| format | Article |
| id | doaj.art-435803f2b681446c9e2127c0219c5cd8 |
| institution | Directory Open Access Journal |
| issn | 1388-0209 1744-5116 |
| language | English |
| last_indexed | 2024-12-19T05:47:54Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Pharmaceutical Biology |
| spelling | doaj.art-435803f2b681446c9e2127c0219c5cd82022-12-21T20:33:46ZengTaylor & Francis GroupPharmaceutical Biology1388-02091744-51162021-01-0159120020810.1080/13880209.2021.18716341871634Influence of verapamil on the pharmacokinetics of rotundic acid in rats and its potential mechanismHaihua Shang0Ze Wang1Hong Ma2Yinghui Sun3Xiaoyan Ci4Yuan Gu5Changxiao Liu6Duanyun Si7School of Pharmacy, Shenyang Pharmaceutical UniversityState Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical ResearchState Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical ResearchState Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical ResearchState Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical ResearchState Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical ResearchSchool of Pharmacy, Shenyang Pharmaceutical UniversityState Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical ResearchContext Rotundic acid (RA), a plant-derived pentacyclic triterpene acid, has been reported to possess extensive pharmacological activities. The poor bioavailability limits its further development and potential clinic application. Objective To clarify the potential mechanism for poor oral bioavailability. Materials and methods The single-dose pharmacokinetics of orally administered RA (10 mg/kg) in Sprague–Dawley rats without or with verapamil (25 or 50 mg/kg) were investigated. Additionally, MDCKII-MDR1 and Caco-2 cell monolayers, five recombinant human cytochrome P450 (rhCYP) enzymes (1A2, 2C8, 2C9, 2D6 and 3A4), and rat liver microsomes were also conducted to investigate its potential mechanism. Results Verapamil could significantly affect the plasma concentration of RA. Co-administered verapamil at 25 and 50 mg/kg, the AUC0–∞ increased from 432 ± 64.2 to 539 ± 53.6 and 836 ± 116 ng × h/mL, respectively, and the oral clearance decreased from 23.6 ± 3.50 to 18.7 ± 1.85 and 12.2 ± 1.85 L/h/kg, respectively. The MDCKII-MDR1 cell assay showed that RA might be a P-gp substrate. The rhCYPs experiments indicated that RA was mainly metabolized by CYP3A4. Additionally, verapamil could increase the absorption of RA by inhibiting the activity of P-gp, and slow down the intrinsic clearance of RA from 48.5 ± 3.18 to 12.0 ± 1.06 µL/min/mg protein. Discussion and conclusions These findings indicated that verapamil could significantly affect the pharmacokinetic profiles of RA in rats. It was demonstrated that P-gp and CYP3A were involved in the transport and metabolism of RA, which might contribute to the low oral bioavailability of RA.http://dx.doi.org/10.1080/13880209.2021.1871634drug–drug interactioncyp3ap-gporal bioavailability |
| spellingShingle | Haihua Shang Ze Wang Hong Ma Yinghui Sun Xiaoyan Ci Yuan Gu Changxiao Liu Duanyun Si Influence of verapamil on the pharmacokinetics of rotundic acid in rats and its potential mechanism Pharmaceutical Biology drug–drug interaction cyp3a p-gp oral bioavailability |
| title | Influence of verapamil on the pharmacokinetics of rotundic acid in rats and its potential mechanism |
| title_full | Influence of verapamil on the pharmacokinetics of rotundic acid in rats and its potential mechanism |
| title_fullStr | Influence of verapamil on the pharmacokinetics of rotundic acid in rats and its potential mechanism |
| title_full_unstemmed | Influence of verapamil on the pharmacokinetics of rotundic acid in rats and its potential mechanism |
| title_short | Influence of verapamil on the pharmacokinetics of rotundic acid in rats and its potential mechanism |
| title_sort | influence of verapamil on the pharmacokinetics of rotundic acid in rats and its potential mechanism |
| topic | drug–drug interaction cyp3a p-gp oral bioavailability |
| url | http://dx.doi.org/10.1080/13880209.2021.1871634 |
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