Simultaneous Determination of Three HIV Protease Inhibitors in Plasma and Drug Interactions between St. John''s wort and Indinavir in Rats

• Main Authors: Da-Kong Huang, 黃大剛
• Other Authors: 余秀瑛
• Format: Others
• Language: zh-TW
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/55820520161330001110

碩士 === 國立臺灣大學 === 藥學研究所 === 93 === 英文摘要 St. John’s wort (Hypericum perforatum, SJW) is one of the most popular herbal preparations widely used in the treatment of mild to moderate depression. However, a series of case reports and clinical studies indicate SJW play a role in drug interactions. In some clinical observations, SJW can reduce the plasma concentration of indinavir, a HIV protease inhibitor. In our study, an animal model for the investigation of the herb-drug interactions between SJW and indinavir has been established. By optimizing pH value and acetonitrile content of the mobile phase, a modified high-performance liquid chromatographic (HPLC) method has also been developed for the simultaneously quantitative determination of three HIV protease inhibitors indinavir, saquinavir, and ritonavir in rat plasma. Chromatography was performed using a C18 reversed-phase column. Ultraviolet detection at 215 nm was used. Linearity of the method was obtained in the concentration range of 100-10000 ng/mL for all three HIV protease inhibitors. Herb-drug interactions between SJW and indinavir can be clearly observed in the Wistar rat model. Oral administration of either 150 mg/day or 300 mg/day SJW extracts for 15 days obviously reduced the plasma concentrations of indinavir and changed its certain pharmacokinetic parameters. The area under the curve (AUC) of indinavir decreased significantly from 5.20 �b 1.09 �慊•h•mL-1 to 0.76 �b 0.50 �慊•h•mL-1 or 1.07 �b 0.26 �慊•h•mL-1 after the pretreatment of 150 mg/day or 300 mg/day SJW extracts for 15 days. The maximum plasma concentration (Cmax) of indinavir also decreased from 5.66 �b 0.58 �慊/mL to 1.23 �b 0.68 �慊/mL or 2.00 �b 0.77 �慊/mL. Several case reports suggested that the 3A4 isoform of the cytochrome P450 (CYP3A4) induction is the mechanism for the decrease in SJW exposure, although effects on P-glycoprotein cannot be ruled out. In our study, an animal model for the investigation of the herb-drug interactions between St. John’s wort and indinavir has been established. These observations have important clinical implications for HIV-infected patients receiving indinavir or the other anti-HIV drugs metabolized by CYP3A4. This animal model could be applied to investigate various herb-drug interactions in the future.