Interaction of thiazolidinediones (glitazones) with the ATP-binding cassette transporters P-glycoprotein and breast cancer resistance protein.

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 -