Interaction of thiazolidinediones (glitazones) with the ATP-binding cassette transporters P-glycoprotein and breast cancer resistance protein.
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Interaction of thiazolidinediones (glitazones) with the ATP-binding cassette transporters P-glycoprotein and breast cancer resistance protein. / Weiss, Johanna; Sauer, Alexandra; Herzog, Melanie; Böger, Rainer; Haefeli, Walter E; Benndorf, Ralf.
in: PHARMACOLOGY, Jahrgang 84, Nr. 5, 5, 2009, S. 264-270.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Interaction of thiazolidinediones (glitazones) with the ATP-binding cassette transporters P-glycoprotein and breast cancer resistance protein.
AU - Weiss, Johanna
AU - Sauer, Alexandra
AU - Herzog, Melanie
AU - Böger, Rainer
AU - Haefeli, Walter E
AU - Benndorf, Ralf
PY - 2009
Y1 - 2009
N2 - AIMS: Thiazolidinediones (glitazones) are frequently prescribed antidiabetic drugs commonly used in combination drug regimens. To evaluate the risk of drug-drug interactions, we therefore aimed to systematically investigate the inhibitory and inductive effects of all glitazones on 2 of the most relevant drug transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in vitro. METHODS: The inhibition of P-gp and BCRP was assessed by fluorometric assays quantifying the increase in the intracellular concentration of fluorescent P-gp or BCRP substrates caused by their combination with the glitazones. The induction of mRNA expression was quantified by real-time RT-PCR after the treatment of HuH-7 cells with the respective compounds for 4 days. RESULTS: Rosiglitazone and troglitazone significantly inhibited P-gp and BCRP function and induced mRNA expression of BCRP but not of P-gp. Pioglitazone, which exhibited very low solubility, could only be tested up to 0.5 micromol/l and did not provoke an effect in any of the assays. CONCLUSIONS: After comparison of the in vitro data and published clinical studies, it seems unlikely that the inhibition of BCRP and P-gp by rosiglitazone plays a role in the clinical situation. In contrast, BCRP induction by rosiglitazone might be of relevance in vivo, but has to be verified in dedicated clinical studies.
AB - AIMS: Thiazolidinediones (glitazones) are frequently prescribed antidiabetic drugs commonly used in combination drug regimens. To evaluate the risk of drug-drug interactions, we therefore aimed to systematically investigate the inhibitory and inductive effects of all glitazones on 2 of the most relevant drug transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in vitro. METHODS: The inhibition of P-gp and BCRP was assessed by fluorometric assays quantifying the increase in the intracellular concentration of fluorescent P-gp or BCRP substrates caused by their combination with the glitazones. The induction of mRNA expression was quantified by real-time RT-PCR after the treatment of HuH-7 cells with the respective compounds for 4 days. RESULTS: Rosiglitazone and troglitazone significantly inhibited P-gp and BCRP function and induced mRNA expression of BCRP but not of P-gp. Pioglitazone, which exhibited very low solubility, could only be tested up to 0.5 micromol/l and did not provoke an effect in any of the assays. CONCLUSIONS: After comparison of the in vitro data and published clinical studies, it seems unlikely that the inhibition of BCRP and P-gp by rosiglitazone plays a role in the clinical situation. In contrast, BCRP induction by rosiglitazone might be of relevance in vivo, but has to be verified in dedicated clinical studies.
KW - Animals
KW - Humans
KW - inhibitors
KW - Mice
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - ATP-Binding Cassette Transporters antagonists
KW - Cell Line, Tumor
KW - Fluorometry
KW - Hypoglycemic Agents pharmacology
KW - P-Glycoprotein antagonists
KW - RNA, Messenger metabolism
KW - Thiazolidinediones pharmacology
KW - Animals
KW - Humans
KW - inhibitors
KW - Mice
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - ATP-Binding Cassette Transporters antagonists
KW - Cell Line, Tumor
KW - Fluorometry
KW - Hypoglycemic Agents pharmacology
KW - P-Glycoprotein antagonists
KW - RNA, Messenger metabolism
KW - Thiazolidinediones pharmacology
M3 - SCORING: Zeitschriftenaufsatz
VL - 84
SP - 264
EP - 270
IS - 5
M1 - 5
ER -