Decreased Intestinal CYP3A and P-glycoproteîn Activities in Rats with Adjuvant Arthritis

• Published in: Drug metabolism and pharmacokinetics Vol. 22; no. 4; pp. 313 - 321
• Main Authors: Uno, Satoshi, Kawase, Atsushi, Tsuji, Akiko, Tanino, Tadatoshi, Iwaki, Masahiro
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2007
• Subjects: adjuvant-induced arthritis; Animals; Antipyrine - metabolism; Arthritis, Experimental - metabolism; ATP Binding Cassette Transporter, Sub-Family B - metabolism; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Blotting, Western; Chromatography, High Pressure Liquid; CYP3A; Cytochrome P-450 CYP3A - metabolism; Diffusion Chambers, Culture; Female; Fluorescent Dyes; In Vitro Techniques; intestine; Intestines - enzymology; Intestines - metabolism; mdrla; Microsomes - drug effects; Microsomes - enzymology; Microsomes - metabolism; Midazolam - metabolism; P-glycoprotein; Ranitidine - pharmacokinetics; rat; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Rhodamine 123; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RT-PCR; P-glycoprotein; CYP3A; intestine; rat; RT-PCR; adjuvant-induced arthritis; mdrla
• ISSN: 1347-4367; 1880-0920
• 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 l′-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) activitiy 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 mdrla 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.