Preincubation Time-Dependent, Long-Lasting Inhibition of Drug Transporters and Impact on the Prediction of Drug−Drug Interactions

Abstract

E 2 G, estradiol-17β-glucuronide; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; HBV, hepatitis B virus; HDV, hepatitis D virus; HEK293, human embryonic kidney 293; IC 50 , half maximal inhibitory concentration; K i , inhibition constant; K p,uu , intracellular-to-extracellular or tissue-to-plasma unbound drug concentration ratio; LAT, L-type amino acid transporter; MATE, multidrug and toxin extrusion; MDCK, Madin-Darby canine kidney; MHLW, Ministry of Health, Labour and Welfare; NTCP, Na + /taurocholate cotransporting polypeptide; OAT, organic anion transporter; OATP/Oatp, organic anion transporting polypeptide; OCT, organic cation transporter; SLC, solute carrier; statin, 3hydroxy-3-methylglutaryl-CoA reductase inhibitor; TCA, taurocholic acid; TDI, time-dependent inhibition; TLC, taurolithocholic acid.

Assessing Trans-Inhibition of OATP1B1 and OATP1B3 by Calcineurin and/or PPIase Inhibitors and Global Identification of OATP1B1/3-Associated Proteins

“…From the transporter regulation perspective, Table 2 summarizes identified OATP1B1and OATP1B3-accociated proteins related to biological processes and proteins relevant to drugs with trans-inhibitory effects on OATP1B1/3 that are reported previously [8,16] or in the current study and are intuitively linked to a potential regulatory mechanism of OATP1B1/3. At present, the best-known factors involved in the regulation of OATP1B1/3 that are also applicable in the HEK293 system are the kinase activator [7,72] and inhibitor [13] compounds, as reviewed in the recent International Transporter Consortium white paper [66].…”

“…Preincubation-induced trans -inhibitory effects [ 7 , 8 , 9 , 10 , 11 ] on OATP1B1 and/or OATP1B3 (abbreviated as OATP1B1/3) have been reported in vitro by many drugs/compounds, where OATP1B1/3-mediated substrate transport is reduced after inhibitor preincubation and washing, when determined in the absence of the inhibitor in the transport assay. OATP1B1 and OATP1B3 are phosphorylated proteins [ 7 , 12 ].…”

“…Some kinase modulator drugs/compounds such as protein kinase C activator [ 7 ] and tyrosine kinase inhibitor nilotinib [ 13 , 14 ] down-regulate OATP1B1/3 transport function under trans -inhibition conditions via modulating kinase activity. Many of the inhibitors with trans -inhibitory effects on OATP1B1/3 were also reported to cause time-dependent inhibition of OATP1B1/3 [ 3 , 4 , 8 , 9 , 10 , 11 , 15 , 16 ], where inhibitor preincubation enhances the inhibitory effect of the inhibitor, resulting in a reduced IC 50 /inhibition constant (K i ). Among inhibitors with trans - and/or time-dependent inhibitory effects on OATP1B1/3, the immunosuppressant calcineurin inhibitor (CNI) CsA has garnered the most attention, being highlighted in the US FDA final guidance to industry [ 17 ], due to its importance in causing clinically significant DDIs against many OATP1B1/3 drug substrates including statins [ 5 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

TICBase: Integrated Resource for Data on Drug and Environmental Chemical Interactions with Mammalian Drug Transporters

“…As outlined above, some of the remaining challenges in using human pharmacokinetic parameters and plasma-concentration time curves for in vitro to in vivo extrapolation and physiologicallybased pharmacokinetic modeling (to better predict transportermediated disposition and elimination of drugs and other xenobiotics within the body) are related to confounding factors, such as organ-and tissue-specific differences in compound concentrations, substrate-and time-dependent transporter inhibition, [61][62][63] plasma protein binding, and bioavailability, 64,65 as well as age-dependent transporter gene expression levels [39][40][41] and interindividual and interethnic differences in genetic polymorphism. 10,36,37 A future version of TransPortal-TICBase is anticipated to include polymorphic transporter gene variants to personalize interaction prediction.…”