Transport characteristics and transporter-based drug-drug interactions of TM-25659, a novel TAZ modulator

• Published in: Biopharmaceutics & drug disposition 2014-04, Vol.35 (3), p.183-194
• Main Authors: Choi, Min-Koo, Kwon, Mihwa, Ahn, Jin Hee, Kim, Nak Jung, Bae, Myung-Ae, Song, Im-Sook
• Format: Article
• Language: English
• Subjects: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Biological Transport; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics; Caco-2 Cells; Dogs; Drug Interactions; drug-drug interactions; hepatobiliary excretion; Hepatocytes - metabolism; Humans; Inhibitory Concentration 50; Madin Darby Canine Kidney Cells; Membrane Transport Proteins - metabolism; Microsomes, Liver - metabolism; Organic Anion Transporters - metabolism; TAZ modulator; Tetrazoles - administration & dosage; Tetrazoles - pharmacokinetics; TM-25659; Transcription Factors - metabolism; transport mechanism; Xenopus laevis
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.1883

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. Copyright © 2013 John Wiley & Sons, Ltd.