title: Contribution of organic anion transporting polypeptide OATP2B1 to amiodarone accumulation in lung epithelial cells.
abstract: The accumulation mechanisms of amiodarone (AMD) involving transporters in lung alveolar epithelial type II cells were studied. The uptake of AMD was examined using human alveolar epithelial-derived cell line A549 as a model. AMD was transported by the carrier-mediated system, and the apparent K(m) and V(max) values were 66.8+/-30.3 muM and 49.7+/-9.7 nmol/mg protein/5 min, respectively. The uptake of AMD by A549 cells was Na(+)-independent and was inhibited by substrates of human organic anion transporting polypeptide (OATP). The inhibition profiles were similar to the inhibitory effects of several compounds on OATP2B1-mediated E-3-S transport, and RT-PCR analysis showed mRNA expression of OATP2B1 and 1B3 in A549 cells. SiRNAs targeted to the OATP2B1 gene decreased the OATP2B1 mRNA expression level in A549 cells up to about 50% and reduced the uptake of AMD up to about 40%. These results indicate that AMD uptake mediated by carriers, including OATP2B1, might lead to accumulation of AMD in the lung and AMD-induced pulmonary toxicity (AIPT).
authors.affiliation: Department of Clinical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Seki
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Shirou
authors.initials: S
authors.lastname: Itagaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirano
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
mesh_terms: D000638:Amiodarone / Q000493:pharmacokinetics* / Q000633:toxicity; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000633:toxicity; D001483:Base Sequence; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000889:Anti-Arrhythmia Agents; D017931:DNA Primers; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C450859:SLCO2B1 protein, human; D000638:Amiodarone