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Repeated administration of berberine inhibits cytochromes P450 in humans

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European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

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 Cmax, AUC0–∞, and AUC0–12 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 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 < 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.

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Acknowledgments

We would like to thank all members of Dr. Klaassen’s laboratory for reviewing this short communication. This work was supported by the following grants: National Institute of Health (ES-009649, ES-019487, DK-081461, and RR021940); National Scientific Foundation of China (No. 30801421); Hunan Provincial Innovation Foundation For Postgraduates (No. 2009bsxt020); Huge Project to Boost Chinese Drug Development (No. 2009ZX09501-032); 863 Projects (No. 2009AA022710, 2009AA022703, 2009AA022704)

Conflict of interest

The authors report no conflict of interest.

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Authors and Affiliations

  1. 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

    Ying Guo, Yao Chen, Zhi-rong Tan & Hong-hao Zhou

  2. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 4099 HLSIC; MS1018; 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA

    Ying Guo & Curtis D. Klaassen

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  1. Ying Guo
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  2. Yao Chen
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  3. Zhi-rong Tan
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  4. Curtis D. Klaassen
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  5. Hong-hao Zhou
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Corresponding authors

Correspondence to Curtis D. Klaassen or Hong-hao Zhou.

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Guo, Y., Chen, Y., Tan, Zr. et al. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol 68, 213–217 (2012). https://doi.org/10.1007/s00228-011-1108-2

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  • DOI: https://doi.org/10.1007/s00228-011-1108-2

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