title: Repeated administration of berberine inhibits cytochromes P450 in humans.
abstract: OBJECTIVE
  Berberine is a plant alkaloid that is widely used to treat gastrointestinal infections, diabetes, hypertension, and hypercholesterolemia. Many studies have reported interactions between berberine-containing products and cytochromes P450 (CYPs), but little is known about whether berberine alters CYP activities in humans, especially after repeated doses.
  
  
  METHODS
  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.
  
  
  RESULTS
  A decrease in CYP2D6 activity was observed as the 0-8 h urinary dextromethorphan/dextrorphan increased ninefold (P < 0.01). In addition, losartan/E-3174 ratio doubled (P < 0.01) after BBR administration, indicating a decrease in CYP2C9 activity. CYP3A4 activity was also inhibited, as the C(max), AUC(0-∞), and AUC(0-12) of midazolam were increased 38% (P < 0.05), 40% (P < 0.01), and 37% (P < 0.05) after BBR treatment, respectively. Compared with the placebo period, the T(max) and T(1/2) 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 < 0.05); and the phenotypic indices of 1 h midazolam/1'-hydroxymidazolam increased 59% (P < 0.01). There were no statistically significant differences in the pharmacokinetic parameters of the other probe drugs between placebo and the BBR-treated group.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, XiangYa School of Medicine, 110 Xiang-Ya Road, Changsha, Hunan 410078, People's Republic of China. yguo2@kumc.edu
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Tan
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
authors.forename: Hong-Hao
authors.initials: HH
authors.lastname: Zhou
mesh_terms: D000328:Adult; D001599:Berberine / Q000493:pharmacokinetics*; D002110:Caffeine / Q000097:blood / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D065607:Cytochrome P-450 Enzyme Inhibitors; D003915:Dextromethorphan / Q000493:pharmacokinetics / Q000652:urine; D004347:Drug Interactions; D004365:Drugs, Chinese Herbal / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D019808:Losartan / Q000493:pharmacokinetics / Q000652:urine; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D001599:Berberine; D002110:Caffeine; D003915:Dextromethorphan; D019808:Losartan; D009853:Omeprazole; D008874:Midazolam