Pharmacokinetic and pharmacodynamic drug-drug interaction of Nomilin with atorvastatin in hyperlipidemic mice
Atorvastatin (Atv) is widely used to lower cholesterol levels and treat hyperlipidemia in clinical application. Nomilin (Nom) is a kind of limonoids, which is found and isolated from the citrus herbs of Rutaceae family, which are widely used as patent medicines, functional foods, and nutritional sup...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844023092241 |
| _version_ | 1797429754268221440 |
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| author | Yan Ding Huida Guan Yingxuan Yan Yan Chen Cheng Huang |
| author_facet | Yan Ding Huida Guan Yingxuan Yan Yan Chen Cheng Huang |
| author_sort | Yan Ding |
| collection | DOAJ |
| description | Atorvastatin (Atv) is widely used to lower cholesterol levels and treat hyperlipidemia in clinical application. Nomilin (Nom) is a kind of limonoids, which is found and isolated from the citrus herbs of Rutaceae family, which are widely used as patent medicines, functional foods, and nutritional supplements in many countries. In previous studies, Nom has the effect of anti-obesity and curing other metabolic diseases. Nevertheless, in recent years, the drug-drug interaction (DDI) caused by the administration of drugs with synergistic effects have raised worldwide concerns. To investigate the DDI of Nom and Atv in vivo, the pharmacokinetic studies were performed with using C57BL/6 mice. The plasma concentrations of Nom and Atv were measured after oral administration of different drug combinations by a simple and sensitive UHPLC-MS/MS method. The experimental mice were randomly divided into five groups, including control group, model group, administered Nom individually group, administered Atv individually group and co-administered of Nom and Atv group. The lipid levels including total cholesterol (TC), triglycerides (TG), high density lipoproteins-cholesterol (HDL-C), low density lipoproteins-cholesterol (LDL-C) were measured for pharmacodynamic study. The hepatic microsomal Cytochrome P450 (CYP1A2, CYP2E1 and CYP3A11) activities were probed using cocktail assay. The gene and protein expressions of CYP3A11 were detected via qPCR and Western blot method. The results shown that the area under the plasma concentration-time curve (AUC) of Atv in administered Atv individually group was 69.30 ± 15.45 ng/mL × h, while that of combined Nom with Atv group was 42.37 ± 10.15 ng/mL × h (p＜0.05). The degree of reduction in lipid levels of mice treated with co-administration of Atv and Nom was less than that of mice treated with Atv alone. In addition, Nom could cause an increased hepatic microsomal CYP3A11 activity significantly, and induce the gene levels and protein expressions of CYP3A11 elevated in mice livers. In conclusion, Nom could up-regulate CYP3A11 activity, thereby impacting on the pharmacokinetic profile and pharmacodynamic effect of Atv. The findings provide more insight for the use risk of these two drugs to treat hyperlipidemia diseases. |
| first_indexed | 2024-03-09T09:17:41Z |
| format | Article |
| id | doaj.art-4e3947f5b7034407ad6ce17f9702f02a |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-03-09T09:17:41Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
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| series | Heliyon |
| spelling | doaj.art-4e3947f5b7034407ad6ce17f9702f02a2023-12-02T07:04:56ZengElsevierHeliyon2405-84402023-11-01911e22016Pharmacokinetic and pharmacodynamic drug-drug interaction of Nomilin with atorvastatin in hyperlipidemic miceYan Ding0Huida Guan1Yingxuan Yan2Yan Chen3Cheng Huang4School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, ChinaInstitute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, ChinaSchool of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, ChinaInstitute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, ChinaSchool of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China; Corresponding author.Atorvastatin (Atv) is widely used to lower cholesterol levels and treat hyperlipidemia in clinical application. Nomilin (Nom) is a kind of limonoids, which is found and isolated from the citrus herbs of Rutaceae family, which are widely used as patent medicines, functional foods, and nutritional supplements in many countries. In previous studies, Nom has the effect of anti-obesity and curing other metabolic diseases. Nevertheless, in recent years, the drug-drug interaction (DDI) caused by the administration of drugs with synergistic effects have raised worldwide concerns. To investigate the DDI of Nom and Atv in vivo, the pharmacokinetic studies were performed with using C57BL/6 mice. The plasma concentrations of Nom and Atv were measured after oral administration of different drug combinations by a simple and sensitive UHPLC-MS/MS method. The experimental mice were randomly divided into five groups, including control group, model group, administered Nom individually group, administered Atv individually group and co-administered of Nom and Atv group. The lipid levels including total cholesterol (TC), triglycerides (TG), high density lipoproteins-cholesterol (HDL-C), low density lipoproteins-cholesterol (LDL-C) were measured for pharmacodynamic study. The hepatic microsomal Cytochrome P450 (CYP1A2, CYP2E1 and CYP3A11) activities were probed using cocktail assay. The gene and protein expressions of CYP3A11 were detected via qPCR and Western blot method. The results shown that the area under the plasma concentration-time curve (AUC) of Atv in administered Atv individually group was 69.30 ± 15.45 ng/mL × h, while that of combined Nom with Atv group was 42.37 ± 10.15 ng/mL × h (p＜0.05). The degree of reduction in lipid levels of mice treated with co-administration of Atv and Nom was less than that of mice treated with Atv alone. In addition, Nom could cause an increased hepatic microsomal CYP3A11 activity significantly, and induce the gene levels and protein expressions of CYP3A11 elevated in mice livers. In conclusion, Nom could up-regulate CYP3A11 activity, thereby impacting on the pharmacokinetic profile and pharmacodynamic effect of Atv. The findings provide more insight for the use risk of these two drugs to treat hyperlipidemia diseases.http://www.sciencedirect.com/science/article/pii/S2405844023092241AtorvastatinCytochrome P450Drug-drug interactionNomilinPharmacodynamicsPharmacokinetics |
| spellingShingle | Yan Ding Huida Guan Yingxuan Yan Yan Chen Cheng Huang Pharmacokinetic and pharmacodynamic drug-drug interaction of Nomilin with atorvastatin in hyperlipidemic mice Heliyon Atorvastatin Cytochrome P450 Drug-drug interaction Nomilin Pharmacodynamics Pharmacokinetics |
| title | Pharmacokinetic and pharmacodynamic drug-drug interaction of Nomilin with atorvastatin in hyperlipidemic mice |
| title_full | Pharmacokinetic and pharmacodynamic drug-drug interaction of Nomilin with atorvastatin in hyperlipidemic mice |
| title_fullStr | Pharmacokinetic and pharmacodynamic drug-drug interaction of Nomilin with atorvastatin in hyperlipidemic mice |
| title_full_unstemmed | Pharmacokinetic and pharmacodynamic drug-drug interaction of Nomilin with atorvastatin in hyperlipidemic mice |
| title_short | Pharmacokinetic and pharmacodynamic drug-drug interaction of Nomilin with atorvastatin in hyperlipidemic mice |
| title_sort | pharmacokinetic and pharmacodynamic drug drug interaction of nomilin with atorvastatin in hyperlipidemic mice |
| topic | Atorvastatin Cytochrome P450 Drug-drug interaction Nomilin Pharmacodynamics Pharmacokinetics |
| url | http://www.sciencedirect.com/science/article/pii/S2405844023092241 |
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