title: Pretreatment With Rifampicin and Tyrosine Kinase Inhibitor Dasatinib Potentiates the Inhibitory Effects Toward OATP1B1- and OATP1B3-Mediated Transport.
abstract: Present studies determined the effects of pretreatment with rifampicin, an organic anion-transporting polypeptide (OATP) inhibitor, and the tyrosine kinase inhibitor dasatinib on OATP1B1- and OATP1B3-mediated transport, and evaluated the OATP-mediated drug-drug interaction potential of dasatinib using the static R-value and dynamic physiologically based pharmacokinetic models. Rifampicin and dasatinib pretreatment significantly decreased OATP1B1- and OATP1B3-mediated transport. Rifampicin pretreatment also significantly decreased [3H]-pitavastatin and [3H]-CCK-8 accumulation in human sandwich-cultured hepatocytes. Present studies revealed that estrone-3-sulfate is a less-sensitive OATP1B1 substrate than estradiol-17β-glucuronide in assessing rifampicin pretreatment effects. Pretreatment with rifampicin and dasatinib reduced the inhibition constant (Ki) values against OATP1B1 by 3 and 2.1 fold and against OATP1B3 by 2.4 and 2.1 fold, respectively. The in vitro rifampicin Kivalues after preincubation are comparable to the estimated in vivo Kireported previously. Models predict that dasatinib has a low potential to cause OATP1B1- and OATP1B3-mediated drug-drug interactions. Time-lapse confocal microscopy demonstrated that rifampicin and dasatinib pretreatment did not affect plasma membrane localization of green-fluorescent protein-tagged OATP1B1 (GFP-OATP1B1) and GFP-OATP1B3 in human embryonic kidney 293 stable cell lines. In summary, we report novel findings that pretreatment with rifampicin and dasatinib potentiates the inhibitory effects toward OATP1B1 and OATP1B3 without affecting plasma membrane levels of the transporters.
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73117.
authors.forename: Sonia
authors.initials: S
authors.lastname: Pahwa
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73117.
authors.forename: Khondoker
authors.initials: K
authors.lastname: Alam
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73117.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Crowe
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73117.
authors.forename: Taleah
authors.initials: T
authors.lastname: Farasyn
authors.affiliation: Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield S2 4SU, UK.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Neuhoff
authors.affiliation: Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield S2 4SU, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hatley
authors.affiliation: Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73126.
authors.forename: Kai
authors.initials: K
authors.lastname: Ding
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73117. Electronic address: wei-yue@ouhsc.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Yue
mesh_terms: D001693:Biological Transport, Active / Q000187:drug effects; D002478:Cells, Cultured; D000069439:Dasatinib / Q000494:pharmacology*; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D047428:Protein Kinase Inhibitors; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000069439:Dasatinib; D012293:Rifampin
keywords: drug interactions; drug transport; hepatic transport; hepatocytes; organic anion-transporting polypeptide transporters; pharmacokinetics; physiologically based pharmacokinetic modeling