Goldenseal (Hydrastis canadensis)
Repeated administration of berberine inhibits cytochromes P450 in humans
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Authors proposed mechanism:
Inhibitory effect of berberine on CYP2D6 activity may be caused by substrate competition.
CYP2C9 did not metabolize berberine, further study about berberine and CYP2C9 gene regulation may provide evidence to clarify this alteration.
CYP3A4 inhibition might be caused by berberine slowing the motility of the digestive system or suppressed mRNA expression
Abstract:
Purpose 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.
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 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.
1 . CYP2D6 Experiment (id=NPDI-8px6rQ)
In Vivo Interaction Study
Increased systemic exposure was detected.
dextromethorphan 1119510
berberine 19012197
- CYP2D6 4173631
Results
Table 1 - Note above is CHANGE FROM CONTROL percent while the paper reports a ratio percent of the two values
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing
Healthy volunteers
Males
No alcohol drinking
Nonsmokers
Asian
17
All Chinese. "All of the subjects were free of other medications, caffeine- and alcohol-containing products as well as grapefruit prior to and during the study."
Urine samples of 0–4, 4–8, 8–12 h
Drug or Natural Product Administration
Oral
Capsule
30 mg
Once Daily
14 days administered at 8 AM with first daily dose of precipitant
Oral
Capsule
900 mg
300 mg three times daily (8 am, 4 pm, 11 pm)
14 days
Yunnan Baiyao Group Dali Pharmaceutical, Yunnan, China
2011
2 . CYP2C9 Experiment (id=NPDI-M8kbsQ)
In Vivo Interaction Study
Increased systemic exposure was detected.
- CYP2C9 4309227
Results
Table 1 - Note above is CHANGE FROM CONTROL percent while the paper reports a ratio percent of the two values
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing
Healthy volunteers
Males
No alcohol drinking
Nonsmokers
Asian
17
Chinese
Urine samples of 0–4, 4–8, 8– 12 h
Drug or Natural Product Administration
Oral
Tablet
30 mg
Once daily
14 days administered at 8 AM with first daily dose of precipitant
Oral
Capsule
900 mg
300 mg three times daily
14 days
Yunnan Baiyao Group Dali Pharmaceutical, Yunnan, China
2011
3 . CYP3A4 Experiment (id=NPDI-j7Vnlw)
In Vivo Interaction Study
Increased systemic exposure was detected.
- CYP3A4 4306811
Results
Table 1 - Note above is CHANGE FROM CONTROL percent while the paper reports a ratio percent of the two values
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing
Healthy volunteers
Males
No alcohol drinking
Nonsmokers
Asian
17
Chinese
0, 0.25,0.5,0.75,1,1.5,2,3,4,6,8,10,and12 h
Blood
Drug or Natural Product Administration
Oral
Tablet
2 mg
Once daily
14 days administered at 8 AM with first daily dose of precipitant
Oral
Capsule
900 mg
300 mg three times daily
14 days
Yunnan Baiyao Group Dali Pharmaceutical, Yunnan, China
2011
4 . CYP1A2 Experiment (id=NPDI-3VbSWA)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
- CYP1A2 4312402
Results
Cmax and AUC -> converted from µg (in paper) to ng for repo (Table 1)
Note above is CHANGE FROM CONTROL percent while the paper reports a ratio percent of the two values
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing
Healthy volunteers
Males
No alcohol drinking
Nonsmokers
Asian
17
Chinese
0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 h
Blood
Drug or Natural Product Administration
Oral
Drink
93 mg
once daily
14 days administered at 8 AM with first daily dose of precipitant
Oral
capsule
900 mg
Three times daily
14 days
Not specified
"Standard cup of coffee"
5 . CYP2C19 Experiment (id=NPDI-nzhlHQ)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
berberine 19012197
- CYP2C19 4311137
Results
Cmax and AUC-> converted from µg (in paper) to ng in repo (Table 1)
Note above is CHANGE FROM CONTROL percent while the paper reports a ratio percent of the two values
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing
Healthy volunteers
Males
No alcohol drinking
Nonsmokers
Asian
17
Chinese
0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 h
Blood
Drug or Natural Product Administration
Oral
Unspecified
20 mg
Once daily
14 days administered at 8 AM with first daily dose of precipitant
Oral
Capsule
900 mg
300 mg three times daily
14 days
Yunnan Baiyao Group Dali Pharmaceutical, Yunnan, China
Unspecified