Decreased intestinal CYP3A and P-glycoprotein activities in rats with adjuvant arthritis

Drug Metab Pharmacokinet. 2007 Aug;22(4):313-21. doi: 10.2133/dmpk.22.313.


Adjuvant-induced arthritis (AA) rats have been used as an animal model for rheumatoid arthritis. Several studies have shown that the pharmacokinetics of a number of drugs are altered in AA rats. We investigated the effects of AA on the barrier functions of the intestine using a rat model. Intestinal CYP3A activities (midazolam 1'-hydroxylation and 7-benzyloxy-4-(trifluoromethyl)-coumarin 7-hydroxylation) in AA rats were significantly decreased compared with those in normal rats, with marked decrease observed in the upper segment of intestine. Intestinal P-glycoprotein (P-gp) activity at upper segment was also significantly decreased in AA rats to 60% of that in normal rats, and the other segments (middle and lower) of intestine also exhibited tendencies toward decrease in P-gp activity. This decrease was supported by the finding that levels of mdr1a mRNA and P-gp protein were decreased in AA rats. No significant differences were observed in intestinal paracellular and transcellular permeability between AA and normal rats. These results suggest that intestinal CYP3A and P-gp activities are decreased in AA rats, and that the pharmacokinetics and bioavailabilities of drugs whose membrane permeation is limited by intestinal CYP3A and/or P-gp may be altered in rheumatic diseases.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Antipyrine / metabolism
  • Arthritis, Experimental / metabolism*
  • Blotting, Western
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP3A / metabolism*
  • Diffusion Chambers, Culture
  • Female
  • Fluorescent Dyes
  • In Vitro Techniques
  • Intestinal Mucosa / metabolism
  • Intestines / enzymology
  • Microsomes / drug effects
  • Microsomes / enzymology
  • Microsomes / metabolism
  • Midazolam / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Ranitidine / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rhodamine 123


  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Fluorescent Dyes
  • RNA, Messenger
  • Rhodamine 123
  • Ranitidine
  • multidrug resistance protein 3
  • Cytochrome P-450 CYP3A
  • Midazolam
  • Antipyrine