TY - JOUR
T1 - Up-regulation of renal Mdr1 and Mrp2 transporters during amiodarone pretreatment in rats
AU - Cermanova, Jolana
AU - Fuksa, Leos
AU - Brcakova, Eva
AU - Hroch, Milos
AU - Kucera, Otto
AU - Kolouchova, Gabriela
AU - Hirsova, Petra
AU - Malakova, Jana
AU - Staud, Frantisek
AU - Martinkova, Jirina
AU - Cervinkova, Zuzana
AU - Micuda, Stanislav
N1 - Funding Information:
This study was supported by grants from Ministry of Education Nos. OC09072-COST B25.001 and MSM 0021620820 .
PY - 2010/2
Y1 - 2010/2
N2 - 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.
AB - 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.
KW - Amiodarone
KW - Cyp3a2
KW - Mdr1
KW - Mdr2
KW - Mrp2
KW - Rhodamine-123
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U2 - 10.1016/j.phrs.2009.08.005
DO - 10.1016/j.phrs.2009.08.005
M3 - Article
C2 - 19703566
AN - SCOPUS:73949097567
SN - 1043-6618
VL - 61
SP - 129
EP - 135
JO - Pharmacological Research
JF - Pharmacological Research
IS - 2
ER -