TITLE:
Radix Polygoni Multiflori Praeparata and Dioscorea Bulbifera Rhizome Decoctions Display Combined Effects Detected by a Three-Probe Drug Cocktail with Substrates of Rat Hepatic Cytochrome P450 Enzymes
AUTHORS:
Li Jiang, Pingping Shan, Hui Yu, Jiayuan Tao, Chunyan Gong, Guoqing Shen
KEYWORDS:
Radix Polygoni Multiflori Praeparata, Dioscorea Bulbifera Rhizomes, Cytochrome P450, Herb-Drug Interactions, Three-Probe Drug Cocktail
JOURNAL NAME:
Pharmacology & Pharmacy,
Vol.5 No.7,
June
26,
2014
ABSTRACT: Objectives: Radix Polygoni Multiflori
Praeparata (RPMP) and Dioscorea
Bulbifera Rhizomes (DBR) are used in Chinese herbal medicine and have been
frequently reported for adverse reactions on liver. In this research, we aimed
to evaluate in vivo effects of RPMP
and DBR on rat cytochrome P450 enzymes (CYP1A2, CYP2E1 and CYP3A2) with their
respective substrates as probes. Methods: Rats were orally administered RPMP,
DBR and RPMP/DBR combination at 12, 10 and (12 + 10) g/kg, respectively, or
saline as a control, once daily for 7 days. Thereafter, a cocktail containing 10
mg/kg caffeine, 20 mg/kg chlorzoxazone and 10 mg/kg dapsone was tail vein
injected to rats. At defined time points, plasma drug concentrations were
simultaneously evaluated by HPLC. Pharmacokinetic parameters simulated by DAS
software were used to assess RPMP and/or DBR effects on cytochrome P450 enzymes
activity. ANOVA and Dunnett’s test were used for data analysis. Results:
Caffeine metabolism was enhanced in RPMP animals and reduced after pretreatment
with DBR, but no effect was observed in RPMP/DBR combination group. Chlorzoxazone
and dapsone metabolism was enhanced in both RPMP and DBR groups and
consequently in combination group. The data suggested that RPMP independently
induces rat CYP1A2, CYP2E1 and CYP3A2 activity, while DBR independently inhibits
activity of rat CYP1A2 and induces that of CYP2E1 and CYP3A2. RPMP/DBR combination
showed no significant benefit compared with the two drugs alone and even showed
a neutralized effect in CYP1A2 activity. Conclusions: Caution is needed when
RPMP and/or DBR are co-administered with drugs metabolized by human CYP1A2, CYP2E1
and CYP3A4.