Glycyrrhizin accelerates the metabolism of triptolide through induction of CYP3A in rats.
BACKGROUND
Triptolide (TP), a major active component of Tripterygium wilfordii, possesses various pharmacological activities with narrow therapeutic window and severe toxicities. Glycyrrhizin (GL), the principal bioactive ingredient of licorice root extract, has been reported to be concomitantly administered with TP in treatment of rheumatoid arthritis with the aim of potentiated efficacy and reduced toxicity. The aim of the study is to investigate the effect of GL on the pharmacokinetic profiles of TP and related mechanisms.


METHODS
Male and female Wistar rats were randomly divided into two groups: Control group and GL group (pretreated with GL at 100 mg/kg/day for seven consecutive days). After oral administration of TP at a single dose of 450 μg/kg, plasma concentrations of TP were determined using HPLC-MS/MS and pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin 6.3 software. Since CYP3A is the primary isoform of cytochrome P450s responsible for the metabolism of TP, we further determined to what extent ketoconazole (KCZ), a potent CYP3A inhibitor, could influence the effect of GL on the pharmacokinetics of TP by comparing the pharmacokinetic profiles of TP in GL group (pretreated with GL) and GL+KCZ group (pretreated with both GL and KCZ), as well as verified whether pretreatment of GL could induce the activity of hepatic CYP3A by comparing the AUC parameters after intravenous administration of midazolam (MDZ), a typical probe drug for CYP3A, in rats pretreated with vehicle or GL.


RESULTS
Our study revealed marked differences in pharmacokinetic profiling patterns of TP between male and female rats in the Control group; the plasma level of TP in males was far lower than that in females. After pretreatment with GL, the pharmacokinetic profiles of TP were significantly altered in both male and female rats; a remarkable decrease was found in the value of AUC∞, MRT∞ and t1/2 in the GL group, compared with the Control group. But such a decrease was reversed by KCZ; compared with the GL group, the values of AUC∞, MRT∞ and t1/2 were significantly increased in the GL+KCZ group. Pretreatment with GL notably increased the AUC∞ of 1׳-hydroxymidazolam (OH-MDZ) and the ratio of AUC∞ of OH-MDZ to MDZ, demonstrating induction of the activity of CYP3A by GL.


CONCLUSIONS
Pretreatment with GL significantly accelerates the metabolic elimination of TP from the body mainly through induction of hepatic CYP3A activity. These results may help explain why toxicity of TP may be attenuated with concomitant use of GL.
Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; Department of Central Laboratory, Nanjing First Hospital, Nanjing Medical University, 68 Chang Le Road, Nanjing 210006, China.
Ting
T
Tai
Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, 24 Tong Jia Xiang, Nanjing 210009, China.
Xin
X
Huang
Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; School of Pharmacy, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
Yuwen
Y
Su
Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
Jinzi
J
Ji
Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, 24 Tong Jia Xiang, Nanjing 210009, China.
Yijing
Y
Su
Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: beaglejiang@cpu.edu.cn.
Zhenzhou
Z
Jiang
Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: lyzhang@cpu.edu.cn.
Luyong
L
Zhang
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism; D004224:Diterpenes / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004852:Epoxy Compounds / Q000493:pharmacokinetics; D005260:Female; D019695:Glycyrrhizic Acid / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D010616:Phenanthrenes / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry; D029757:Tripterygium / Q000737:chemistry
D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; C001899:triptolide; D019695:Glycyrrhizic Acid; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole
CYP3A; Glycyrrhizin; Glycyrrhizin (PubChem CID: 14982); Ketoconazole (PubChem CID: 47576); Midazolam (PubChem CID: 4192); Pharmacokinetics; Toxicity; Triptolide; Triptolide (PubChem CID: 107985)