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Bioavailability of the Diterpenoid 14-deoxy-11,12-didehydroandrographolide in Rats and Up-Regulation of Hepatic Drug-Metabolizing Enzyme and Drug Transporter Expression

Bioavailability of the Diterpenoid 14-deoxy-11,12-didehydroandrographolide in Rats and Up-Regulation of Hepatic Drug-Metabolizing Enzyme and Drug Transporter Expression

Chih-Ching Yen, Yun-Ta Liu, Ying-Jyan Lin, Ya-Chen Yang, Chien-Chih Chen, Hsien-Tsung Yao, Haw-Wen Chen, Chong-Kuei Lii

Phytomedicine. 2019 Aug;61:152841.

PMID: 31035043

Abstract:

Background:
14-Deoxy-11,12-didehydroandrographolide (deAND) is the second most abundant diterpenoid in Andrographis paniculata (Burm. f.) Nees, a traditional medicine used in Asia. To date, the biological activity of deAND has not been clearly investigated.
Purpose:
In this study, we intended to examine the modulatory effect of deAND on hepatic drug metabolism as well as its bioavailability.
Study design:
deAND prepared from A. paniculata was orally given to Sprague-Dawley rats and changes in plasma deNAD were determined by HPLC-MS. Modulation of deAND on drug-metabolizing enzyme and drug transporter expression as well as the possible mechanism involved was examined in primary rat hepatocytes.
Results:
After a single oral administration of 50 mg/kg deAND to rats, the maximum plasma concentration (Cmax), time to reach the Cmax, area under the curve (AUC0-24h), mean retention time, and half-life (t1/2) of deAND were 2.65 ± 0.68 μg/ml, 0.29 ± 0.15 h, 6.30 ± 1.66 μg/ml•h, 5.55 ± 2.52 h, and 3.56 ± 1.05 h, respectively. The oral bioavailability was 3.42%. In primary rat hepatocytes treated with up to 10 μM deAND, a dose-dependent increase was noted in the expression of cytochrome P450 (CYP) 1A1/2, CYP2C6, and CYP3A1/2; UDP-glucuronosyltransferase (UGT) 1A1, NAD(P)H:quinone oxidoreductase (NQO1), π form of GSH S-transferase (GSTP), multidrug resistance-associated protein 2, p-glycoprotein, and organic anion transporter protein 2B1. Immunoblotting assay and EMSA revealed that deAND increases the nuclear translocation and DNA binding activity of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and nuclear factor erythroid-derived 2-related factor 2 (Nrf2). Knockdown of AhR and Nrf2 expression abolished deAND induction of CYP isozymes and UGT1A1, NQO1, and GSTP expression, respectively.
Conclusion:
These results indicate that deAND quickly passes through enterocytes in rats and effectively up-regulates hepatic drug-metabolizing enzyme and drug transporter expression in an AhR-, PXR-, and Nrf2-dependent manner.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP42895589	14-Deoxy-11,12-didehydroandrographolide		42895-58-9	Price

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