Goldenseal (Hydrastis canadensis) 43525850
Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic study CSV JSON

Objective: To study the effects of berberine (BBR) on the blood concentration and pharmacokinetics of cyclosporin A (CsA) in renal-transplant recipients.
Methods: In a randomized and controlled clinical trial, 52 renal-transplant recipients were treated with CsA and 0.2 g BBR three times daily for 3 months, while another 52 subjects received CsA without BBR co-administration. Blood trough concentration of CsA and biochemistry indexes for hepatic and renal functions were determined. For the pharmacokinetic study, six renal transplant recipients were included with a 3-mg/kg dosage of CsA twice daily before and after oral co- administration of 0.2 g BBR three times daily for 12 days.
Results: The trough blood concentrations and the ratios of concentration/dose of CsA in the BBR-treated group increased by 88.9% and 98.4%, respectively, compared with those at baseline (P<0.05). As for the BBR-free group, they rose by 64.5% and 69.4%, respectively, relative to those at baseline (P<0.01). Nevertheless, the final blood concentrations and the ratios of concentration/dose of CsA in BBR-treated patients were still 29.3% and 27.8%, respectively, higher than those in BBR-free patients (P<0.05). No significant effects on liver or renal functions were observed under coadministration of BBR. After co-administra- tion of BBR in six patients for 12 days, the mean AUC of CsA was increased by 34.5% (P<0.05). The mean time taken to reach the peak blood concentration (tmax) and the mean half-life (t1/2) of CsA were increased by 1.7 h and 2.7 h, respectively (P<0.05). The average percentage increases in the steady-state drug con- centration (Css) and minimum blood concentration (Cmin) were 34.5% and 88.3%, respectively (P<0.05). In addition, the average percentage decrease in CL/F was 40.4% (P<0.05) and the peak-to-through fluctuation index was significantly reduced (P<0.01).

Conclusion: The BBR can markedly elevate the blood concentration of CsA in renal-transplant recipients in both clinical and pharmacokinetic studies. This combination may allow a reduction of the CsA dosage. The mechanism for this interaction is most likely explained by inhibition of CYP3A4 by BBR in the liver and/or small intestine.

1 . CsA in Renal Transplant patients (id=NPDI-uJn2xw)

In Vivo Interaction Study

Increased systemic exposure was detected.

cyclosporin A

Berberine 19012197

Results

Table 5

Fluctuation Index: Control - 2.8 (0.6) Test 1.4 (0.7) p<0.01

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Fixed-sequence
Parallel
Multiple dosing

Population

Females
Males
Patients

6

Within 1 month after receiving the renal transplant operation, six recipients (three males and three females) were selected—44.0±4.5 years in age, 165.2±8.8 cm in height and 59.0±13.9 kg in weight. All had normal hepatic function. They had been treated orally with 3 mg/kg CsA (twice per day) for 12.7±5.9 days before the start of the trial.

Pharmacokinetic (PK) Sampling Information

0, 2, 4, 6, 8,10, 12 hours

Drug or Natural Product Administration

Object Administration — cyclosporin A

Oral

capsule

6 mg/kg

Twice Daily

13 days

Precipitant Administration — Berberine

Oral

tablet

600 mg

three times daily

13 days

Natural Product Characteristics

unspecified

Pharmacodynamics (PD) & Adverse Events

Gastrointestinal disorders 35700000

Constipation (n=3)

2 . CsA Trough measurements in 52 patients (id=NPDI-C2C-Nw)

In Vivo Interaction Study

Increased systemic exposure was detected.

cyclosporin A

Berberine 19012197

Results

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Parallel
Multiple dosing

Population

Females
Males
Patients

52

Characteristics:

Age (years) 42.5±10.8
Body weight (kg) 55.3±10.2
Body mass index (kg/m2) 20.5±3.4
Sex (male/female) 31/21
Cyclosporin A dosage (mg/day) 319.2±90.7
Duration of cyclosporin A (months)  2.7±2.4
Azathioprine (mg/day) 43.4±17.4 
Prednisone (mg/day)  12.0±4.1

 

Pharmacokinetic (PK) Sampling Information

0, 2, 4, 6, 8,10, 12 hours

Drug or Natural Product Administration

Object Administration — cyclosporin A

Oral

capsule

6 mg/kg

Twice Daily

3 months

Precipitant Administration — Berberine

Oral

tablet

600 mg

three times daily

3 months

Natural Product Characteristics

unspecified