Goldenseal (Hydrastis canadensis) 43525850
Repeated administration of berberine inhibits cytochromes P450 in humans CSV JSON

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

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing

Population

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."

Pharmacokinetic (PK) Sampling Information

Urine samples of 0–4, 4–8, 8–12 h

Drug or Natural Product Administration

Object Administration — dextromethorphan

Oral

Capsule

30 mg

Once Daily

14 days administered at 8 AM with first daily dose of precipitant

Precipitant Administration — Berberine

Oral

Capsule

900 mg

300 mg three times daily (8 am, 4 pm, 11 pm)

14 days

Natural Product Characteristics

Yunnan Baiyao Group Dali Pharmaceutical, Yunnan, China

2011

2 . CYP2C9 Experiment (id=NPDI-M8kbsQ)

In Vivo Interaction Study

Increased systemic exposure was detected.

losartan

Berberine 19012197

  • CYP2C9 4309227

Results

Table 1 - Note above is CHANGE FROM CONTROL percent while the paper reports a ratio percent of the two values

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing

Population

Healthy volunteers
Males

No alcohol drinking
Nonsmokers

Asian

17

Chinese

Pharmacokinetic (PK) Sampling Information

Urine samples of 0–4, 4–8, 8– 12 h

Drug or Natural Product Administration

Object Administration — losartan

Oral

Tablet

30 mg

Once daily

14 days administered at 8 AM with first daily dose of precipitant

Precipitant Administration — Berberine

Oral

Capsule

900 mg

300 mg three times daily

14 days

Natural Product Characteristics

Yunnan Baiyao Group Dali Pharmaceutical, Yunnan, China

2011

3 . CYP3A4 Experiment (id=NPDI-j7Vnlw)

In Vivo Interaction Study

Increased systemic exposure was detected.

midazolam 708298

Berberine 19012197

  • CYP3A4 4306811

Results

Table 1 - Note above is CHANGE FROM CONTROL percent while the paper reports a ratio percent of the two values

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing

Population

Healthy volunteers
Males

No alcohol drinking
Nonsmokers

Asian

17

Chinese

Pharmacokinetic (PK) Sampling Information

0, 0.25,0.5,0.75,1,1.5,2,3,4,6,8,10,and12 h

Blood

Drug or Natural Product Administration

Object Administration — midazolam

Oral

Tablet

2 mg

Once daily

14 days administered at 8 AM with first daily dose of precipitant

Precipitant Administration — Berberine

Oral

Capsule

900 mg

300 mg three times daily

14 days

Natural Product Characteristics

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.

caffeine 1134439

Berberine 19012197

  • 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

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing

Population

Healthy volunteers
Males

No alcohol drinking
Nonsmokers

Asian

17

Chinese

Pharmacokinetic (PK) Sampling Information

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

Object Administration — caffeine

Oral

Drink

93 mg

once daily

14 days administered at 8 AM with first daily dose of precipitant

Precipitant Administration — Berberine

Oral

capsule

900 mg

Three times daily

14 days

Natural Product Characteristics

Not specified

"Standard cup of coffee"

5 . CYP2C19 Experiment (id=NPDI-nzhlHQ)

In Vivo Interaction Study

No Effect (based on bioequivalence limits) was detected.

omeprazole

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

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing

Population

Healthy volunteers
Males

No alcohol drinking
Nonsmokers

Asian

17

Chinese

Pharmacokinetic (PK) Sampling Information

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

Object Administration — omeprazole

Oral

Unspecified

20 mg

Once daily

14 days administered at 8 AM with first daily dose of precipitant

Precipitant Administration — Berberine

Oral

Capsule

900 mg

300 mg three times daily

14 days

Natural Product Characteristics

Yunnan Baiyao Group Dali Pharmaceutical, Yunnan, China

Unspecified