title: Transport characteristics and transporter-based drug-drug interactions of TM-25659, a novel TAZ modulator.
abstract: The in vitro metabolic stability and transport mechanism of TM-25659, a novel TAZ modulator, was investigated in human hepatocytes and human liver microsomes (HLMs) based on the preferred hepatobiliary elimination in rats. In addition, the in vitro transport mechanism and transporter-mediated drug-drug interactions were evaluated using oocytes and MDCKII cells overexpressing clinically important drug transporters. After a 1 h incubation in HLMs, 92.9 ± 9.5% and 95.5 ± 11.6% of the initial TM-25659 remained in the presence of NADPH and UDPGA, respectively. Uptake of TM-25659 readily accumulated in human hepatocytes at 37 ºC (i.e. 6.7-fold greater than that at 4 ºC), in which drug transporters such as OATP1B1 and OATP1B3 were involved. TM-25659 had a significantly greater basal to apical transport rate (5.9-fold) than apical to basal transport rate in the Caco-2 cell monolayer, suggesting the involvement of an efflux transport system. Further studies using inhibitors of efflux transporters and overexpressing cells revealed that MRP2 was involved in the transport of TM-25659. These results, taken together, suggested that TM-25659 can be actively influxed into hepatocytes and undergo biliary excretion without substantial metabolism. Additionally, TM-25659 inhibited the transport activities of OATP1B1 and OATP1B3 with IC50 values of 36.3 and 25.9 μm, respectively. TM-25659 (100 μm) increased the accumulation of the probe substrate by 160% and 213%, respectively, through the inhibition of efflux function of P-gp and MRP2. In conclusion, OATP1B1, OATP1B3, P-gp and MRP2 might be major transporters responsible for the pharmacokinetics and drug-drug interaction of TM-25659, although their contribution to in vivo pharmacokinetics needs to be further investigated.
authors.affiliation: College of Pharmacy, Dankook University, Cheonan, Korea.
authors.forename: Min-Koo
authors.initials: MK
authors.lastname: Choi
authors.forename: Mihwa
authors.initials: M
authors.lastname: Kwon
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Nak Jung
authors.initials: NJ
authors.lastname: Kim
authors.forename: Myung-Ae
authors.initials: MA
authors.lastname: Bae
authors.forename: Im-Sook
authors.initials: IS
authors.lastname: Song
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000217:Acyltransferases; D000818:Animals; D001692:Biological Transport; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D004285:Dogs; D004347:Drug Interactions; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D061985:Madin Darby Canine Kidney Cells; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014157:Transcription Factors / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: C572937:2-butyl-5-methyl-6-(pyridine-3-yl)-3-(2'-(1H-tetrazole-5-yl)-biphenyl-4-ylmethyl)-3H-imidazo(4,5-b)pyridine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019086:Bridged Bicyclo Compounds, Heterocyclic; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D013777:Tetrazoles; D014157:Transcription Factors; D000217:Acyltransferases; C544439:Tafazzin protein, rat
keywords: TAZ modulator; TM-25659; drug-drug interactions; hepatobiliary excretion; transport mechanism