Abstract | PURPOSE: METHODS: Induction of transporters and enzymes was quantified at the mRNA level by real-time RT-PCR in LS180 cells and for P-gp also at the protein level by Western blot. P-gp inhibition was evaluated by calcein assay in P388/dx and L-MDR1 cells and BCRP inhibition in MDCKII-BCRP cells by pheophorbide A efflux. Substrate characteristics were evaluated by growth inhibition assays in MDCKII cells overexpressing particular ABC-transporters. RESULTS:
Atrasentan profoundly induced several CYPs and drug transporters (e.g. 12-fold induction of CYP3A4 at 50 μM). It was a moderate P-gp inhibitor (IC(50) in P388/dx cells = 15.1 ± 1.6 μM) and a weak BCRP inhibitor (IC(50) in MDCKII-BCRP cells = 59.8 ± 11 μM). BCRP or P-gp overexpressing cells were slightly more resistant towards antiproliferative effects of atrasentan. CONCLUSIONS: Our data provide a comprehensive analysis of the induction profile of atrasentan and its interaction with P-gp and BCRP. The profound induction effects stress the need for thorough assessment of its interaction potential in vivo.
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Authors | Johanna Weiss, Walter Emil Haefeli |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 68
Issue 4
Pg. 1093-8
(Oct 2011)
ISSN: 1432-0843 [Electronic] Germany |
PMID | 21805352
(Publication Type: Journal Article)
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Chemical References |
- ABCG2 protein, human
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters
- Antineoplastic Agents
- Endothelin A Receptor Antagonists
- Neoplasm Proteins
- Pyrrolidines
- RNA, Messenger
- Cytochrome P-450 Enzyme System
- Atrasentan
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(antagonists & inhibitors)
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters
(antagonists & inhibitors)
- Animals
- Antineoplastic Agents
(administration & dosage, pharmacology)
- Atrasentan
- Cell Line
- Cell Line, Tumor
- Cytochrome P-450 Enzyme System
(biosynthesis, drug effects)
- Dogs
- Drug Interactions
- Drug Resistance, Multiple
- Endothelin A Receptor Antagonists
- Enzyme Induction
(drug effects)
- Humans
- Inhibitory Concentration 50
- Leukemia P388
(metabolism)
- Mice
- Neoplasm Proteins
(antagonists & inhibitors)
- Pyrrolidines
(administration & dosage, pharmacology)
- RNA, Messenger
(metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
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