title: Comparative pharmacokinetics of rhein in normal and loperamide-induced constipated rats and microarray analysis of drug-metabolizing genes.
abstract: BACKGROUND
  Rhein is a pharmacological active component found in Rheum palmatum L. that is the major herb of the San-Huang-Xie-Xin-Tang (SHXXT), a medicinal herbal product used as a remedy for constipation. Here we have investigated the comparative pharmacokinetics of rhein in normal and constipated rats. Microarray analysis was used to explore whether drug-metabolizing genes will be altered after SHXXT treatment.
  
  
  METHODS
  The comparative pharmacokinetics of rhein in normal and loperamide-induced constipated rats was studied by liquid chromatography with electrospray ionization tandem mass spectrometry (LC-MS/MS). Gene expression profiling in drug-metabolizing genes after SHXXT treatment was investigated by microarray analysis and real-time polymerase chain reaction (RT-PCR).
  
  
  RESULTS
  A validated LC-MS/MS method was applied to investigate the comparative pharmacokinetics of rhein in normal and loperamide-induced constipated rats. The pharmacokinetic results demonstrate that the loperamide-induced constipation reduced the absorption of rhein. Cmax significantly reduced by 2.5-fold, the AUC decreased by 27.8%; however, the elimination half-life (t1/2) was prolonged by 1.6-fold. Tmax and mean residence time (MRT) were significantly prolonged by 2.8-fold, and 1.7-fold, respectively. The volume of distribution (Vss) increased by 2.2-fold. The data of microarray analysis on gene expression indicate that five drug-metabolizing genes, including Cyp7a1, Cyp2c6, Ces2e, Atp1b1, and Slc7a2 were significantly altered by the SHXXT (0.5 g/kg) treatment.
  
  
  CONCLUSIONS
  The loperamide-induced constipation reduced the absorption of rhein. Since among the 25,338 genes analyzed, there were five genes significantly altered by SHXXT treatment. Thus, information on minor drug-metabolizing genes altered by SHXXT treatment indicates that SHXXT is relatively safe for clinical application.
authors.affiliation: Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Hou
authors.affiliation: Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Chang
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Lin
authors.affiliation: National Research Institute of Chinese Medicine, Taipei, Taiwan.
authors.forename: Lie-Chwen
authors.initials: LC
authors.lastname: Lin
authors.affiliation: Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan; Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan; Department of Education and Research, Taipei City Hospital, Taipei, Taiwan. Electronic address: thtsai@ym.edu.tw.
authors.forename: Tung-Hu
authors.initials: TH
authors.lastname: Tsai
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000880:Anthraquinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation / Q000235:genetics*; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D002853:Chromatography, Liquid; D003248:Constipation / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods*; D015971:Gene Expression Regulation, Enzymologic; D006207:Half-Life; D054368:Laxatives / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008139:Loperamide; D008297:Male; D008657:Metabolic Clearance Rate; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D008517:Phytotherapy; D010946:Plants, Medicinal; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013255:Steroid 21-Hydroxylase / Q000235:genetics / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D026923:Amino Acid Transport Systems, Basic; D000880:Anthraquinones; C503554:Atp1b1 protein, rat; D054368:Laxatives; C490274:Slc7a2 protein, rat; D008139:Loperamide; C089877:Cyp2c6v1 protein, rat; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase; C532838:CYP7A1 protein, rat; D002790:Cholesterol 7-alpha-Hydroxylase; D002265:Carboxylic Ester Hydrolases; D000254:Sodium-Potassium-Exchanging ATPase; C020491:rhein
keywords: Loperamide-induced constipation; Microarray; Pharmacokinetics; Rhein; Traditional Chinese medicine