Contribution of baicalin on the plasma protein binding displacement and CYP3A activity inhibition to the pharmacokinetic changes of nifedipine in rats in vivo and in vitro.
Baicalin purified from the root of Radix scutellariae is widely used in clinical practices. This study aimed to evaluate the effect of baicalin on the pharmacokinetics of nifedipine, a CYP3A probe substrate, in rats in vivo and in vitro. In a randomised, three-period crossover study, significant changes in the pharmacokinetics of nifedipine (2 mg/kg) were observed after treatment with a low (0.225 g/kg) or high (0.45 g/kg) dose of baicalin in rats. In the low- and high-dose groups of baicalin-treated rats, C max of total nifedipine decreased by 40%±14% (P<0.01) and 65%±14% (P<0.01), AUC0-∞ decreased by 41%±8% (P<0.01) and 63%±7% (P<0.01), Vd increased by 85%±43% (P<0.01) and 224%±231% (P<0.01), and CL increased by 97%±78% (P<0.01) and 242%±135% (P<0.01), respectively. Plasma protein binding experiments in vivo showed that C max of unbound nifedipine significantly increased by 25%±19% (P<0.01) and 44%±29% (P<0.01), respectively, and there was a good correlation between the unbound nifedipine (%) and baicalin concentrations (P<0.01). Furthermore, in vitro results revealed that baicalin was a competitive displacer of nifedipine from plasma proteins. In vitro incubation experiments demonstrated that baicalin could also competitively inhibit CYP3A activity in rat liver microsomes in a concentration-dependent manner. In conclusion, the pharmacokinetic changes of nifedipine may be modulated by the inhibitory effects of baicalin on plasma protein binding and CYP3A-mediated metabolism.
Department of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, China.
Zhen-Yu
ZY
Cheng
Department of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, China.
Xin
X
Tian
Department of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, China.
Jie
J
Gao
Department of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, China.
Hong-Meng
HM
Li
Department of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, China.
Lin-Jing
LJ
Jia
Department of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, China.
Hai-Ling
HL
Qiao
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D005419:Flavonoids / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009543:Nifedipine / Q000493:pharmacokinetics*; D010936:Plant Extracts / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001798:Blood Proteins; D065692:Cytochrome P-450 CYP3A Inhibitors; D005419:Flavonoids; D010936:Plant Extracts; C038044:baicalin; D009543:Nifedipine