Suppression of drug-metabolizing enzymes and efflux transporters in the intestine of endotoxin-treated rats.
Infection and inflammation impose a suppression in the expression and activity of several drug transporters and drug-metabolizing enzymes in liver. In the intestine, cytochrome P450 3A (CYP3A), P-glycoprotein (PGP/mdr1), and the multidrug resistance-associated protein 2 (MRP2) are important barriers to the absorption of many clinically important drugs; thus, the expression and activity of these proteins were examined in inflammation. Transport and metabolism were determined in jejunum segments isolated at 24 h from endotoxin-treated or control rats (n = 8) mounted in Ussing chambers. Transport and metabolism of (3)H-digoxin, 5-carboxyfluorescein (5-CF), amiodarone (AM), and 7-benzyloxyquinoline (7-BQ) were measured for 90 min in the presence and absence of inhibitors. Reverse transcription-polymerase chain reaction was used to measure mRNA levels. As compared with controls, levels of mdr1a and mrp2 mRNA were significantly decreased by approximately 50% in the jejunum of LPS-treated rats. Corresponding reductions in the basolateral-->apical efflux of digoxin, AM, and 5-CF were observed, resulting in significant increases in the apical-->basolateral absorption of these compounds. Intestinal CYP3A mRNA levels and CYP3A-mediated metabolism of 7-BQ and AM were also decreased by approximately 50 to 70% (p < 0.05) in the LPS group. Mannitol permeability and lactate dehydrogenase release were not altered. These studies indicate that endotoxin-induced inflammation imposes a reduction in the intestinal expression and activity of PGP, mrp2, and CYP3A in rats, which elicits corresponding changes in the intestinal transport and metabolism of their substrates. Hence, infection and inflammatory diseases may impose variability in drug bioavailability through alterations in the intestinal expression and activity of drug transporters and metabolic enzymes.
Kalitsky-Szirtes
J
J
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada M5S 2S2.
Shayeganpour
A
A
Brocks
D R
DR
Piquette-Miller
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters; D000638:Amiodarone / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D004077:Digoxin / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D005452:Fluoresceins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011804:Quinolines / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015262:Xenobiotics / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000889:Anti-Arrhythmia Agents; D002352:Carrier Proteins; D004731:Endotoxins; D005452:Fluoresceins; D008070:Lipopolysaccharides; D004364:Pharmaceutical Preparations; D011804:Quinolines; D012333:RNA, Messenger; D015262:Xenobiotics; C065956:7-benzyloxyquinoline; D004077:Digoxin; C045132:4-carboxyfluorescein; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000638:Amiodarone