Activation of P-glycoprotein and CYP 3A by Coptidis Rhizoma in vivo: Using cyclosporine as a probe substrate in rats

Coptidis Rhizoma (CR), the rhizome of Coptis chinensis FRANCH, is a popular Chinese herb. CR contains plenty of isoquinoline alkaloids such as berberine, coptisine and palmatine. Cyclosporine (CSP), an important immunosuppressant with narrow therapeutic window, is employed as a probe substrate of P-...

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Published in:	Yàowu shi͡p︡in fenxi 2018-04, Vol.26 (2), p.S125-S132
Main Authors:	Yu, Chung-Ping, Huang, Ching-Ya, Lin, Shiuan-Pey, Hou, Yu-Chi
Format:	Article
Language:	eng
Subjects:	Alkaloids Berberine Bioavailability Blood Blood levels Cyclosporine Cyclosporins Cytochrome P450 3A Drug dosages Efflux Fluorescence Fluorescence polarization Glycoproteins Herb–drug interactions Immunoassay In vivo methods and tests Laboratory animals Metabolites Oral administration Original P-Glycoprotein Pharmacokinetics Proteins Rats Substrates
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Summary:	Coptidis Rhizoma (CR), the rhizome of Coptis chinensis FRANCH, is a popular Chinese herb. CR contains plenty of isoquinoline alkaloids such as berberine, coptisine and palmatine. Cyclosporine (CSP), an important immunosuppressant with narrow therapeutic window, is employed as a probe substrate of P-glycoprotein (P-gp) and CYP3A4 in order to investigate the in vivo modulation effect of CR on P-gp and CYP3A4. Three groups of rats were orally administered CSP without and with single dose or repeated dosing of CR in a parallel design. Blood samples were collected at specific time points and the blood CSP concentration was determined by a specific monoclonal fluorescence polarization immunoassay. The results showed that a single dose (1.0 g/kg) and the 7th dose (1.0 g/kg) of CR significantly decreased the Cmax of CSP by 56.9% and 70.4%, and reduced the AUC0-540 by 56.4% and 68.7%, respectively. Cell study indicated that CR decoction, berberine, coptisine, palmatine all activated the efflux transport of P-gp. Ex-vivo study showed that the serum metabolites of CR activated CYP 3A4. In conclusion, through using CSP as an in vivo probe substrate, we have verified that oral intake of CR activated the functions of P-gp and CYP3A based on in vivo and in vitro studies. [Display omitted] •CR decreased the bioavailability of CSP, a probe substrate of P-gp and CYP 3A.•Coptidis Rhizoma (CR) activated P-gp.•The serum metabolites of CR activated CYP3A4.
ISSN:	1021-9498 2224-6614