Increased systemic exposure to rhizoma coptidis alkaloids in lipopolysaccharide-pretreated rats attributable to enhanced intestinal absorption.

Rhizoma coptidis is a rhizome commonly used in traditional Chinese medicine. After oral administration of rhizoma coptidis extract, the plasma concentrations of its effective alkaloid constituents are so low that their systemic therapeutic actions cannot be explained. This study aimed to investigate the influence of lipopolysaccharide (LPS) on the pharmacokinetics of the rhizoma coptidis alkaloids. Pharmacokinetic experiments were performed with rats; both in vitro absorption and efflux experiments were carried out with everted rat gut sacs, whereas in vitro metabolism experiments were conducted with rat liver microsomes and intestinal S9 fractions. Mucosal changes were evaluated with light microscopy and transmission electron microscopy. The results showed that, in rat plasma, LPS pretreatment increased systemic alkaloid exposure. LPS pretreatment increased the in vitro absorption of the alkaloids and decreased their efflux. The efflux of vinblastine and rhodamine 123, P-glycoprotein substrates, also was decreased. The absorption of fluorescein isothiocyanate-labeled dextran (average molecular mass, 4 kDa), a gut paracellular permeability probe, was not influenced. Obvious damage was observed in the mucosa, but the tight junctions between epithelial cells remained intact. Intestinal, rather than hepatic, alkaloid metabolism was decreased. These findings indicated that LPS pretreatment increased systemic exposure to the alkaloids through enhancement of their absorption, which was related to decreased intestinal efflux and metabolism. The results add to the understanding of why rhizoma coptidis is active despite the low plasma concentrations of the rhizoma coptidis alkaloids measured in normal subjects and experimental animals.

Lipopolysaccharide increased the acute toxicity of the Rhizoma coptidis extract in mice by increasing the systemic exposure to Rhizoma coptidis alkaloids.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhizoma coptidis is used as an antidysenteric in clinics in China. However, patients suffering from dysentery are susceptible to the acute toxicity of Rhizoma coptidis. The current study investigates the effects of lipopolysaccharide (LPS), which are a key pathogenic factor in dysentery, on the acute toxicity of a Rhizoma coptidis extract in mice; possible mechanisms are proposed. MATERIALS AND METHODS: Acute toxicity and pharmacokinetic experiments in mice were conducted. The plasma concentration of Rhizoma coptidis alkaloids in mice was determined using liquid chromatography/tandem mass spectrometry. The activity of acetylcholinesterase (AChE) in the tissue homogenate was determined using an AChE determination kit. RESULTS: Pretreatment with LPS for 16 h increased the acute toxicity of the oral Rhizoma coptidis extract. Systemic exposure to Rhizoma coptidis alkaloids was also increased by LPS pretreatment. Neostigmine significantly increased whereas pyraloxime methylchloride reduced the acute toxicity of the Rhizoma coptidis extract. LPS pretreatment alone showed no significant effect on the activity of thoracoabdominal diaphragm AChE. However, it enhanced the inhibitory effect of the Rhizoma coptidis extract. LPS pretreatment did not affect the acute toxicity of various dosages of tail vein-injected berberine. CONCLUSIONS: LPS increased the acute toxicity of the oral Rhizoma coptidis extract in mice by increasing the systemic exposure to the Rhizoma coptidis alkaloids.