Influence of Zuojin Pill on the Metabolism of Venlafaxine in Vitro and in Rats and Associated Herb-Drug Interaction.

Venlafaxine (VEN), a first-line antidepressant, and Zuojin Pill (ZJP), a common Chinese herbal medicine consisting of Rhizoma Coptidis and Fructus Evodiae, have a high likelihood of combination usage in patients with depression with gastrointestinal complications. ZJP exhibits inhibitory effects on recombinant human cytochrome P450 isoenzymes (rhP450s), especially on CYP2D6, whereas VEN undergoes extensive metabolism by CYP2D6. From this perspective, we investigated the influence of ZJP on the metabolism of VEN in vitro and in rats for the first time. In this study, ZJP significantly inhibited the metabolism of VEN in both rat liver microsomes (RLM) and human liver microsomes (HLM); meanwhile, it inhibited the O-demethylation catalytic activity of RLM, HLM, rhCYP2D6*1/*1, and rhCYP2D6*10/*10, primarily through CYP2D6, with IC50 values of 129.9, 30.5, 15.4, and 2.3 µg/ml, respectively. Furthermore, the inhibitory effects of ZJP on hepatic metabolism and pharmacokinetics of VEN could also be observed in the pharmacokinetic study of rats. The area under drug concentration-time curve0-24 hour of VEN and its major metabolite O-desmethylvenlafaxine (ODV) increased by 39.6% and 22.8%, respectively. The hepatic exposure of ODV decreased by 57.2% 2 hours after administration (P = 0.014). In conclusion, ZJP displayed inhibitory effects on hepatic metabolism and pharmacokinetics of VEN in vitro and in rats mainly through inhibition of CYP2D6 activity. The human pharmacokinetic interaction between ZJP and VEN and its associated clinical significance needed to be seriously considered. SIGNIFICANCE STATEMENT: Zuojin Pill, a commonly used Chinese herbal medicine, demonstrates significant inhibitory effects on hepatic metabolism and pharmacokinetics of venlafaxine in vitro and in rats mainly through suppression of CYP2D6 activity. The human pharmacokinetic interaction between Zuojin Pill and venlafaxine and its associated clinical significance needs to be seriously considered.

The oral bioavailability, excretion and cytochrome P450 inhibition properties of epiberberine: an in vivo and in vitro evaluation.

Epiberberine (EPI) is a novel and potentially effective therapeutic and preventive agent for diabetes and cardiovascular disease. To evaluate its potential value for drug development, a specific, sensitive and robust high-performance liquid chromatography-tandem mass spectrometry assay for the determination of EPI in rat biological samples was established. This assay was used to study the pharmacokinetics, bioavailability and excretion of EPI in rats after oral administration. In addition, a cocktail method was used to compare the inhibition characteristics of EPI on cytochrome P450 (CYP450) isoforms in human liver microsomes (HLMs) and rat liver microsomes (RLMs). The results demonstrated that EPI was rapidly absorbed and metabolized after oral administration (10, 54 or 81 mg/kg) in rats, with Tmax of 0.37-0.42 h and T1/2 of 0.49-2.73 h. The Cmax and area under the curve values for EPI increased proportionally with the dose, and the oral absolute bioavailability was 14.46%. EPI was excreted mainly in bile and feces, and after its oral administration to rats, EPI was eliminated predominantly by the kidneys. A comparison of the current half-maximal inhibitory concentration and Ki values revealed that EPI demonstrated an obvious inhibitory effect on CYP2C9 and CYP2D6. Furthermore, its effect was stronger in HLM than in RLM, more likely to be a result of noncompetitive inhibition.

Enhanced oral bioavailability of metoprolol with gallic acid and ellagic acid in male Wistar rats: involvement of CYP2D6 inhibition.

BACKGROUND: Cytochrome P450-2D6 (CYP2D6), a member of the CYP450 mixed function oxidase system, is an important CYP isoform with regard to herbal-drug interactions and is responsible for the metabolism of nearly 25% of drugs. Until now, studies on the effects of various phytochemicals on CYP2D6 activity in vivo have been very rare. Gallic acid and ellagic acid are natural polyphenols which are widely distributed in fruits and medicinal plants. In the present study, the effects of gallic acid and ellagic acid pretreatment on intestinal transport and oral bioavailability of metoprolol were investigated. METHODS: The intestinal transport of metoprolol was assessed by conducting an in situ single pass intestinal perfusion (SPIP) study. The bioavailability study was conducted to evaluate the pharmacokinetic parameters of orally administered metoprolol in rats. RESULTS: After pretreatment with gallic acid and ellagic acid, no significant change in effective permeability of metoprolol was observed at the ileum part of rat intestine. A significant improvement in the peak plasma concentration (Cmax) and area under the serum concentration-time profile (AUC) and decrease in clearance were observed in rats pretreated with gallic acid and ellagic acid. CONCLUSIONS: Gallic acid and ellagic acid significantly enhanced the oral bioavailability of metoprolol by inhibiting CYP2D6-mediated metabolism in the rat liver. Hence, adverse herbal-drug interactions may result with concomitant ingestion of gallic acid and ellagic acid supplements and drugs that are CYP2D6 substrates. The clinical assessment of these interactions should be further investigated in human volunteers.

Effects of suberoylanilide hydroxamic acid on rat cytochrome P450 enzyme activities.

Vorinostat (suberoylanilide hydroxamic acid, SAHA) is the first approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma after progressive disease following two systemic therapies. The rats were randomly divided into SAHA groups (low, medium and high dosage) and control group. The SAHA group rats were given 12.3, 24.5, and 49 mg/kg SAHA, respectively, by continuous intragastric administration for 7 days. The influence of SAHA on the activities of CYP450 isoforms CYP2B6, CYP1A2, CYP2C19, CYP2D6 and CYP2C9 were evaluated by cocktail method, they were responsed by the changes of pharmacokinetic parameters of bupropion, phenacetin, tolbutamide, metroprolol and omeprazole. The five probe drugs were given to rats through intragastric administration, and the plasma concentration were determined by UPLC-MS/MS. The result of SAHA group compared to control group, there were statistical pharmacokinetics difference for bupropion, phenacetin, tolbutamide and metroprolol. Continuous intragastric administration for 7 days may induce the activities of CYP2C19 of rats, inhibit CYP1A2 and slightly inhibit CYP2B6 and CYP2D6 of rats. This may give advising for reasonable drug use after co-used with SAHA. The results indicated that drug co-administrated with SAHA may need dose adjustment. Furthermore, continuous intragastric administration of SAHA for 7 days, liver cell damaged, causing liver cell edema, in liver metabolism process.

Identification and characterization of potent CYP2D6 inhibitors in lotus leaves.

ETHNOPHARMACOLOGICAL RELEVANCE: The herb of lotus (Nelumbo nucifera) leaves is a commonly used traditional Chinese herbal medicine that is utilized for the treatment of sunstroke, to assuage thirst, and to cure both diarrhea and fever in China. Modern pharmacological studies have demonstrated that the herb exhibits various pharmacological effects, such as anti-hyperlipidemia, anti-obesity, anti-oxidant, anti-HIV, anti-microbial, and anti-hypoglycemic activities. Currently, the herb is becoming more popular in China as a "tea drink" or as a main ingredient of some herbal formulations, which implies that the herb and/or its products are now more likely to be concurrently administered with conventional medicines for losing body weight and reducing blood lipids. However, its potential inhibitory effect on human cytochrome P450 (CYP) has not been systemically investigated to date. The present study was performed to assess the potential inhibitory effects of lotus leaf alcoholic extract (LAE), its major fractions, and its main compounds on five CYP isoenzymes (CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) in vitro. MATERIAL AND METHODS: Five probe substrates were incubated with human liver microsomes in the presence or absence of the LAE, the alkaloid fraction (AF), the flavonoid fraction (FF), or the individual aporphine alkaloids, namely, nuciferine (NF), N-nornuciferine (N-NF), and 2-hydroxy-1-methoxyaporphine (HMA). After the incubation, the relative metabolites of the substrates were analyzed using LC-MS/MS. RESULTS: The results showed that the LAE strongly inhibited CYP2D6 with an IC50 value of 12.05µg/mL and weakly inhibited other isoenzymes. In addition, FF was found to weakly inhibit CYP2D6, whereas AF exerted a markedly higher inhibitory effect on CYP2D6 activity with an IC50 value of 0.96µg/mL. The three aporphine alkaloids isolated from the AF (NF, N-NF, and HMA) significantly inhibited CYP2D6 with IC50 values of 3.78, 3.76, and 3.15µM, respectively. Their Lineweaver-Burk plots and Dixon plots showed that NF, N-NF, and HMA competitively inhibited CYP2D6 activity with Ki values of 1.88, 2.34, and 1.56µM, respectively. CONCLUSION: The study revealed that the alkaloid compounds in lotus leaves exert a potent inhibitory effect on CYP2D6 isoenzyme. The possible drug interactions of the leaves and their preparations with conventional medicines should thus be taken into account.