Abstract
Puerarin (8-β-D-glucopyranosyl-7-hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a
major pharmacological component of Puerariae Radix, the root of Pueraria lobata. We
investigated the effect of puerarin on hepatic cytochrome P450-mediated drug metabolism
in rats
and humans. The in vitro cytochrome P450 inhibitory effect of puerarin in human and rat
liver microsomes was evaluated using the following model cytochrome P450 substrates:
phenacetin
for CYP1A, diclofenac for CYP2C, dextromethorphan for CYP2D, and testosterone for
CYP3A. The
in vivo pharmacokinetics of intravenous and oral buspirone, a probe substrate for
CYP3A, was studied with single simultaneous intravenous coadministration of puerarin
in rats. In
the in vitro cytochrome P450 inhibition study, the rate of disappearance of testosterone
was significantly reduced in the presence of 10 µM PU, while that of other cytochrome
P450
substrates was not significantly affected in both human and rat liver microsomes,
suggesting
that puerarin inhibits the in vitro hepatic CYP3A-mediated metabolism in the human and
rat systems (IC50 = 15.5 ± 3.9 µM). After intravenous administration of buspirone
with single simultaneous coadministration of intravenous puerarin at a dose of 10 mg/kg
in rats,
the total area under the plasma concentration–time curve from time zero to time infinity
was
increased while time-averaged total body clearance decreased. When buspirone was orally
administered in rats with the 10 mg/kg intravenous puerarin coadministration, both
total area
under the plasma concentration–time curve from time zero to time infinity and the
extent of
absolute oral bioavailability were significantly increased. Therefore, results of
the in
vitro microsomal and in vivo pharmacokinetic studies suggest the possible
inhibition of hepatic CYP3A-mediated drug metabolism by puerarin administration, potentially
leading to metabolism-mediated herb–drug interactions with clinical significance.
Key words
puerarin -
Pueraria lobata
- Fabaceae - cytochrome P450 - buspirone - hepatic metabolism - pharmacokinetics
