Up-regulation of renal Mdr1 and Mrp2 transporters during amiodarone pretreatment in rats.
Although amiodarone (AMD) is known to produce drug-drug interactions through inhibition of transporter-mediated excretion of drugs, its impact on these mechanisms during chronic treatment has not been described yet. Therefore, the aim of this study was to investigate the influence of AMD pretreatment on the main multidrug transporting proteins, Mdr1 and Mrp2, in the liver and kidney. The expression of the transporters and pharmacokinetics of their substrates, rhodamine-123 (Rho123) and endogenous conjugated bilirubin (CB), were evaluated in rats after either AMD oral pretreatments (4-14 days) or single intravenous bolus. AMD pretreatment of all durations up-regulated renal Mdr1 and Mrp2 protein expression to 155-190% and 152-223% of the control values, respectively. In agreement, we observed a corresponding increase in renal clearance of both substrates. Hepatic expression was increased only for Mdr1 to 234-270% of controls, which was associated with increased biliary elimination of amiodarone without change in Rho123 biliary clearance. Interestingly, hepatic expression of another Mdr transporter, Mdr2, was progressively decreased by amiodarone administration. Acute administration of AMD reduced Rho123 biliary clearance by 64%. Our results indicate that repeated administration of AMD to rats is associated with significant increase in hepatic and renal expression of Mdr1 and Mrp2 transporters, which may contribute to variability in pharmacokinetics of AMD and simultaneously applied drugs.
Cermanova
Jolana
J
Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic.
Fuksa
Leos
L
Brcakova
Eva
E
Hroch
Milos
M
Kucera
Otto
O
Kolouchova
Gabriela
G
Hirsova
Petra
P
Malakova
Jana
J
Staud
Frantisek
F
Martinkova
Jirina
J
Cervinkova
Zuzana
Z
Micuda
Stanislav
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000284:Administration, Oral; D000638:Amiodarone / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001663:Bilirubin / Q000378:metabolism; D001692:Biological Transport; D015153:Blotting, Western; D002478:Cells, Cultured; D004347:Drug Interactions; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D027361:Organic Anion Transporters / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D015854:Up-Regulation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000889:Anti-Arrhythmia Agents; D027361:Organic Anion Transporters; C503597:Slco1a4 protein, rat; D020112:Rhodamine 123; D000638:Amiodarone; D001663:Bilirubin