Department of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou 450052, China.
J Ethnopharmacol. 2013 Nov 25;150(2):477-84. doi: 10.1016/j.jep.2013.08.062. Epub 2013 Sep 26.
Baicalin is one of the major bioactive constituents of Scutellariae Radix, the root of Scutellariae baicalensis Georgi and possesses a wide variety of pharmacological properties.
To elucidate the effect of baicalin on the pharmacokinetics of theophylline in rats, focusing on plasma protein binding displacement and inhibition effect on CYP1A2 in vivo and in vitro.
The study was a randomized, three-period crossover design. Nine rats were given saline (control) or 450 mg/kg baicalin (dosage regimen A or B). Dosage regimen A was administered once at 0 h. Dosage regimen B was divided into three dosages (225,112.5, 112.5 mg/kg) and was given at 0, 2 and 4 h, respectively. Then theophylline (5 mg/kg, i.v.) was administered immediately. The effect of baicalin on CYP1A2 activity was determined by metabolism of phenacetin in vitro and plasma protein binding of theophylline was determined by ultrafiltration.
C(max) decreased from (12.4 ± 1.6) to (8.7 ± 0.9) and (8.6 ± 2.0) mg/L, T(1/2) increased by 116 and 96%, V(d) increased by 51 and 49% for total theophylline in rats treated with dosage regimen A and B of baicalin, respectively. Cmax was significantly increased, V(d) decreased by 43 and 29% for unbound theophylline in rats treated with dosage regimen A and B of baicalin, respectively (P < 0.01). T(1/2) of unbound theophylline increased by 104% only in rats treated with dosage regimen B. No significant effects on the CL and AUC of both total and unbound theophylline were observed in the rats treated with dosage regimen A, but the CL decreased and AUC increased for total theophylline and CL decreased for unbound theophylline in the group treated with dosage regimen B (P < 0.05). Correlation analysis showed that the mean unbound theophylline (%) and mean baicalin concentration was in good correlation (P < 0.01). Baicalin decreased metabolism of phenacetin and exhibited a mixed-type inhibition in rat liver microsomes, with a K(i) value of 88.1 μM in vitro. Moreover baicalin was a competitive displacer of theophylline from plasma protein in vitro.
The changes in Cmax, T(1/2), CL and AUC of theophylline due to baicalin may be attributed to two mechanisms, plasma protein binding displacement and CYP1A2 activity inhibition.
黄芩苷是黄芩的主要生物活性成分之一，黄芩为唇形科植物黄芩的根，具有广泛的药理作用。
阐明黄芩苷对大鼠茶碱药代动力学的影响，重点研究体内外血浆蛋白结合置换和对 CYP1A2 的抑制作用。
本研究采用随机、三周期交叉设计。9 只大鼠分别给予生理盐水（对照）或 450mg/kg 黄芩苷（方案 A 或 B 剂量）。方案 A 于 0h 时单次给药。方案 B 分为 3 个剂量（225、112.5、112.5mg/kg），分别于 0、2 和 4h 给药，然后立即给予茶碱（5mg/kg，iv）。通过体外测定对乙酰氨基酚的代谢来确定黄芩苷对 CYP1A2 活性的影响，通过超滤法测定茶碱的血浆蛋白结合。
与对照组相比，方案 A 和 B 处理的大鼠中总茶碱的 Cmax 分别降低了（12.4±1.6）→（8.7±0.9）和（8.6±2.0）mg/L，T1/2 分别增加了 116%和 96%，Vd 分别增加了 51%和 49%。方案 A 和 B 处理的大鼠中，未结合茶碱的 Cmax 显著增加，Vd 分别降低了 43%和 29%（P<0.01）。仅在方案 B 处理的大鼠中，未结合茶碱的 T1/2 增加了 104%。方案 A 处理的大鼠中，总茶碱和未结合茶碱的 CL 和 AUC 均无显著变化，但方案 B 处理的大鼠中，总茶碱的 CL 降低，AUC 增加，未结合茶碱的 CL 降低（P<0.05）。相关性分析表明，平均未结合茶碱（%）和平均黄芩苷浓度呈良好相关（P<0.01）。黄芩苷在体外可降低对乙酰氨基酚的代谢，并在大鼠肝微粒体中表现出混合抑制作用，K(i)值为 88.1μM。此外，黄芩苷在体外是茶碱从血浆蛋白中的竞争性置换剂。
由于黄芩苷，茶碱的 Cmax、T1/2、CL 和 AUC 的变化可能归因于两种机制，即血浆蛋白结合置换和 CYP1A2 活性抑制。
