[{"id":59,"uid":"NPDI-5XFThQ","name":"Repeated administration of berberine inhibits cytochromes P450 in humans","napdiIdentifier":"PMID: 21870106","overallSummary":"<div class=\"page\" title=\"Page 3\">\r\n<div class=\"layoutArea\">\r\n<div class=\"column\">\r\n<p>Authors proposed mechanism:<br /><br />Inhibitory effect of berberine on CYP2D6 activity may be caused by substrate competition.<br />CYP2C9 did not metabolize berberine, further study about berberine and CYP2C9 gene regulation may provide evidence to clarify this alteration.<br />CYP3A4 inhibition might be caused by berberine slowing the motility of the digestive system or suppressed mRNA expression<br /><br />Abstract:<br /><em>Purpose</em> Berberine is a plant alkaloid that is widely used to treat gastrointestinal infections, diabetes, hypertension, and hypercholesterolemia. Many studies have reported interac- tions between berberine-containing products and cyto- chromes P450 (CYPs), but little is known about whether berberine alters CYP activities in humans, especially after repeated doses.<br /><em>Methods</em> A two-phase randomized-crossover clinical study in healthy male subjects was performed. After 2 weeks of berberine (300 mg, t.i.d., p.o.) administration, midazolam, omeprazole, dextromethorphan, losartan, and caffeine were used to evaluate enzyme activities of CYP3A4, 2C19, 2D6, 2C9, and CYP1A2, respectively.<br /><em>Results</em> A decrease in CYP2D6 activity was observed as the 0–8 h urinary dextromethorphan/dextrorphan increased ninefold (P &lt; 0.01). In addition, losartan/E-3174 ratio doubled (P &lt; 0.01) after BBR administration, indicating a decrease in CYP2C9 activity. CYP3A4 activity was also inhibited, as the Cmax, AUC0–∞, and AUC0–12 of midazolam were increased 38% (P &lt; 0.05), 40% (P &lt; 0.01), and 37% (P &lt; 0.05) after with the placebo period, the Tmax and T1/2 of midazolam during BBR administration were prolonged from 3.03 ± 0.27 to 3.66 ± 0.37 h and 0.66 ± 0.08 to 0.99 ± 0.09 h, respectively; the oral clearance of midazolam was decreased 27% (P&lt; 0.05); and the phenotypic indices of 1 h midazolam/1′- hydroxymidazolam increased 59% (P &lt; 0.01). There were no statistically significant differences in the pharmacokinetic parameters of the other probe drugs between placebo and the BBR-treated group.<br /><em>Conclusions</em> Repeated administration of berberine (300 mg, t.i.d., p.o.) decreased CYP2D6, 2C9, and CYP3A4 activities. Drug-drug interactions should be considered when berberine is administered.</p>\r\n</div>\r\n</div>\r\n</div>","pubmedId":21870106,"embaseId":null,"croIdentifier":"XiangYa School of Medicine","croInformation":"Institute of Clinical Pharmacology","dateStart":null,"dateEnd":null,"internalComment":null,"status":"published","compoundId":null,"naturalProductUid":"NP-002d7e9a-2baf-47cb-a936-51ba9cbb36a7","naturalProductSampleId":null,"studySourceTypeId":1,"naturalProduct":{"uid":"NP-002d7e9a-2baf-47cb-a936-51ba9cbb36a7","binomial":"Hydrastis canadensis","name":"Goldenseal","itis":null,"srs":"66690655-f406-4d67-96e3-2066aafee8d5","source_id":"","conceptId":null},"compound":null,"studySourceType":{"id":1,"name":"Published report"},"experiments":[{"id":271,"uid":"NPDI-8px6rQ","name":"CYP2D6 Experiment","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":null,"croIdentifier":null,"comment":null,"experimentalConditionsComment":null,"resultsComment":"Table 1 - Note above is CHANGE FROM CONTROL percent while the paper reports a ratio percent of the two values","internalComment":null,"objectCompoundId":12,"objectMetaboliteCompoundId":null,"precipitantCompoundId":80,"cytochromeB5Id":null,"studyId":59,"experimentTypeId":9,"testSystemId":null,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":9,"name":"In Vivo 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while the paper reports a ratio percent of the two values","internalComment":null,"objectCompoundId":61,"objectMetaboliteCompoundId":null,"precipitantCompoundId":80,"cytochromeB5Id":null,"studyId":59,"experimentTypeId":9,"testSystemId":null,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":9,"name":"In Vivo 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two values","internalComment":null,"objectCompoundId":26,"objectMetaboliteCompoundId":null,"precipitantCompoundId":80,"cytochromeB5Id":null,"studyId":59,"experimentTypeId":9,"testSystemId":null,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":9,"name":"In Vivo 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<strong>µ</strong>g (in paper) to ng for repo (Table 1)<br /><br />Note above is CHANGE FROM CONTROL percent while the paper reports a ratio percent of the two values","internalComment":null,"objectCompoundId":7,"objectMetaboliteCompoundId":null,"precipitantCompoundId":80,"cytochromeB5Id":null,"studyId":59,"experimentTypeId":9,"testSystemId":null,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":9,"name":"In Vivo 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