Asian Journal of Pharmacodynamics and Pharmacokinetics

Xu HY et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2009; 9(1):11-25
hepatobiliary excretion, an in vivo microdialysis
coupled with HPLC was performed. In the control
group, rats received berberine alone; in the
drug-treated group, 10 min before berberine
administration, the rats were injected with
cyclosporin A (CsA), a P-gp inhibitor; quinidine,
both organic cation transport (OCT) and P-gp
inhibitors; SKF-525A (proadifen), a cytochrome
P450 inhibitor; and probenecid to inhibit the
glucuronidation. The results indicate that berberine
displays a linear pharmacokinetic phenomenon in the
dosage range from 10 to 20 mg·kg -1 , since a
proportional increase in the area under the
concentration-time curve (AUC) of berberine was
observed in this dosage range. Moreover, berberine
was processed through hepatobiliary excretion
against a concentration gradient based on the
bile-to-blood distribution ratio (AUC bile /AUC blood );
the active berberine efflux might be affected by P-gp
and OCT since coadministration of berberine and
CsA or quinidine at the same dosage of 10 mg·kg -1
significantly decreased the berberine amount in bile.
In addition, berberine was metabolized in the liver
with phase I demethylation and phase II
glucuronidation, as identified by liquid
chromatography/tandem mass spectrometry. Also, the
phase I metabolism of berberine was partially
reduced by SKF-525A treatment, but the phase II
glucuronidation of berberine was not obviously
affected by probenecid under the present study
design. [44]
In order to investigate the pharmacokinetics of
berberine in Coptidis rhizoma extract in rat
hippocampus and plasma, a simple and accurate
high-performance liquid chromatography method was
employed in this study. Berberine was determined
using a Hypersil C 18 column with an isocratic mobile
phase of acetonitrile-0.05 M potassium dihydrogen
phosphate (containing 0.5% triethylamine, pH 3.0)
and with UV detection at 236 nm. The lower limit of
quantification for berberine in both hippocampus and
plasma was 24 ng·ml -1 , and the lowest concentrations
of berberine determined in rat hippocampus and
plasma samples were 30.7 ng·mL -1 at 48 h and 38.5
ng·mL -1 at 4 h, respectively. The calibration curve for
berberine was linear over the concentration range
24--6000 ng·mL -1 . At this concentration range, the
overall recoveries (90.6--94.2%) for berberine were
determined and the accuracy of intra- and inter-day
assays from rat samples were less than 7% RSD.
Following intravenous administration of C. rhizoma
extract at a dose of 10.2 mg/kg containing 3 mg/kg
berberine, berberine in the plasma eliminated rapidly
t 1/2β =1.13 h). However, berberine in the hippocampus
increased rapidly t 1/2α =0.215 h), peaked at 3.67 h with
a concentration of 272 ng·g -1 , and had a slow
elimination rate t 1/2β =12.0 h), which suggests that
berberine could have a direct action on neuron and
accumulate in the hippocampus. This study first
showed the pharmacokinetic characteristics of
berberine in rat hippocampus and the kinetic
characteristics of berberine are dissimilar in the
hippocampus and plasma. [45]
To study the effects of berberine (BBR) on the
blood concentration and pharmacokinetics of
cyclosporin A (CsA) in renal-transplant recipients., a
randomized and controlled clinical trial was carried
out in 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. 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 co-administration of
BBR. After co-administration of BBR in 6 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 (T max ) and the mean
half-life (t 1/2 ) 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 concentration (C ss )
and minimum blood concentration (C min ) were 34.5%
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