Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption
Background: Sorafenib (SOR) is an oral, potent, selective, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used as the first-line therapy for advanced hepatocellular carcinoma (HCC). Baicalin (BG) is used as adjuvant therapy for hepatitis, which accounts for the le...
Guardado en:
| Autores principales: | , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Frontiers Media S.A.
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/4a48cab5eb4c44fbbdb5dd4acb8b1158 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:4a48cab5eb4c44fbbdb5dd4acb8b1158 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:4a48cab5eb4c44fbbdb5dd4acb8b11582021-11-08T07:07:03ZBaicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption1663-981210.3389/fphar.2021.761763https://doaj.org/article/4a48cab5eb4c44fbbdb5dd4acb8b11582021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.761763/fullhttps://doaj.org/toc/1663-9812Background: Sorafenib (SOR) is an oral, potent, selective, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used as the first-line therapy for advanced hepatocellular carcinoma (HCC). Baicalin (BG) is used as adjuvant therapy for hepatitis, which accounts for the leading cause of the development of HCC, and is commonly coadministered with SOR in clinic. The purpose of the current study was to characterize the pharmacokinetic changes of SOR and the potential mechanism when SOR is administered concomitantly with BG in rats for single and multiple doses.Methods: Parallel randomized pharmacokinetic studies were performed in rats which received SOR (50 mg/kg, i.g.) alone or coadministered with BG (160 mg/kg, i.g.) for single and multiple doses (7 days). Plasma SOR levels were quantified by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Rat liver microsomes (RLMs) which isolated from their livers were analyzed for CYP3A and SOR metabolism activities. The inhibitory effect of BG on the metabolism of SOR was also assessed in pooled human liver microsomes (HLMs). The effects of BG on the intestine absorption behaviors of SOR were assessed in the in situ single-pass rat intestinal perfusion model.Results: Coadministration with BG (160 mg/kg, i.g.) for single or multiple doses significantly increased the Cmax, AUC0–t, and AUC0–∞ of orally administered SOR by 1.68-, 1.73-, 1.70-fold and 2.02-, 1.65-, 1.66- fold in male rats and by 1.85-, 1.68-, 1.68-fold and 1.57-, 1.25-, 1.24- fold in female rats, respectively (p < 0.01 or p < 0.05). In vitro incubation assays demonstrated that there were no significant differences of Km, Vmax, and CLint of 1-OH MDZ and SOR N-oxide in RLMs between control and multiple doses of BG-treated groups. BG has no obvious inhibitory effects on the metabolism of SOR in HLMs. In comparison with SOR alone, combining with BG significantly increased the permeability coefficient (Peff) and absorption rate constant (Ka) of the SOR in situ single-pass rat intestinal perfusion model.Conclusion: Notably enhanced oral bioavailability of SOR by combination with BG in rats may mainly account for BG-induced SOR absorption. A greater understanding of potential DDIs between BG and SOR in rats makes major contributions to clinical rational multidrug therapy in HCC patients. Clinical trials in humans and HCC patients need to be further confirmed in the subsequent study.Jingyao WeiJingyao WeiRuijuan LiuRuijuan LiuJiali ZhangJiali ZhangShuaibing LiuShuaibing LiuDan YanDan YanXueqian WenXueqian WenXin TianXin TianFrontiers Media S.A.articlebaicalinsorafenibbioavailabilitydrug–drug interactionsin situ single-pass rat intestinal perfusion modelTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
baicalin sorafenib bioavailability drug–drug interactions in situ single-pass rat intestinal perfusion model Therapeutics. Pharmacology RM1-950 |
| spellingShingle |
baicalin sorafenib bioavailability drug–drug interactions in situ single-pass rat intestinal perfusion model Therapeutics. Pharmacology RM1-950 Jingyao Wei Jingyao Wei Ruijuan Liu Ruijuan Liu Jiali Zhang Jiali Zhang Shuaibing Liu Shuaibing Liu Dan Yan Dan Yan Xueqian Wen Xueqian Wen Xin Tian Xin Tian Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption |
| description |
Background: Sorafenib (SOR) is an oral, potent, selective, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used as the first-line therapy for advanced hepatocellular carcinoma (HCC). Baicalin (BG) is used as adjuvant therapy for hepatitis, which accounts for the leading cause of the development of HCC, and is commonly coadministered with SOR in clinic. The purpose of the current study was to characterize the pharmacokinetic changes of SOR and the potential mechanism when SOR is administered concomitantly with BG in rats for single and multiple doses.Methods: Parallel randomized pharmacokinetic studies were performed in rats which received SOR (50 mg/kg, i.g.) alone or coadministered with BG (160 mg/kg, i.g.) for single and multiple doses (7 days). Plasma SOR levels were quantified by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Rat liver microsomes (RLMs) which isolated from their livers were analyzed for CYP3A and SOR metabolism activities. The inhibitory effect of BG on the metabolism of SOR was also assessed in pooled human liver microsomes (HLMs). The effects of BG on the intestine absorption behaviors of SOR were assessed in the in situ single-pass rat intestinal perfusion model.Results: Coadministration with BG (160 mg/kg, i.g.) for single or multiple doses significantly increased the Cmax, AUC0–t, and AUC0–∞ of orally administered SOR by 1.68-, 1.73-, 1.70-fold and 2.02-, 1.65-, 1.66- fold in male rats and by 1.85-, 1.68-, 1.68-fold and 1.57-, 1.25-, 1.24- fold in female rats, respectively (p < 0.01 or p < 0.05). In vitro incubation assays demonstrated that there were no significant differences of Km, Vmax, and CLint of 1-OH MDZ and SOR N-oxide in RLMs between control and multiple doses of BG-treated groups. BG has no obvious inhibitory effects on the metabolism of SOR in HLMs. In comparison with SOR alone, combining with BG significantly increased the permeability coefficient (Peff) and absorption rate constant (Ka) of the SOR in situ single-pass rat intestinal perfusion model.Conclusion: Notably enhanced oral bioavailability of SOR by combination with BG in rats may mainly account for BG-induced SOR absorption. A greater understanding of potential DDIs between BG and SOR in rats makes major contributions to clinical rational multidrug therapy in HCC patients. Clinical trials in humans and HCC patients need to be further confirmed in the subsequent study. |
| format |
article |
| author |
Jingyao Wei Jingyao Wei Ruijuan Liu Ruijuan Liu Jiali Zhang Jiali Zhang Shuaibing Liu Shuaibing Liu Dan Yan Dan Yan Xueqian Wen Xueqian Wen Xin Tian Xin Tian |
| author_facet |
Jingyao Wei Jingyao Wei Ruijuan Liu Ruijuan Liu Jiali Zhang Jiali Zhang Shuaibing Liu Shuaibing Liu Dan Yan Dan Yan Xueqian Wen Xueqian Wen Xin Tian Xin Tian |
| author_sort |
Jingyao Wei |
| title |
Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption |
| title_short |
Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption |
| title_full |
Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption |
| title_fullStr |
Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption |
| title_full_unstemmed |
Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption |
| title_sort |
baicalin enhanced oral bioavailability of sorafenib in rats by inducing intestine absorption |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/4a48cab5eb4c44fbbdb5dd4acb8b1158 |
| work_keys_str_mv |
AT jingyaowei baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption AT jingyaowei baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption AT ruijuanliu baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption AT ruijuanliu baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption AT jializhang baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption AT jializhang baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption AT shuaibingliu baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption AT shuaibingliu baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption AT danyan baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption AT danyan baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption AT xueqianwen baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption AT xueqianwen baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption AT xintian baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption AT xintian baicalinenhancedoralbioavailabilityofsorafenibinratsbyinducingintestineabsorption |
| _version_ |
1718442905312428032 |