Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters.
OBJECTIVE
To compare side-by-side the uptake of sorafenib and sunitinib in vitro by human uptake solute carriers of the SLC22A and SLCO families, the transport by and inhibition of efflux ATP-binding cassette (ABC) transporters, and the role of ABCB1 in the plasma pharmacokinetics and brain penetration of these agents.


METHODS
Uptake of [(3)H]sorafenib or [(3)H]sunitinib was assessed in Xenopus laevis oocytes or mammalian cells transfected with cDNAs coding for human OATP1A2, OATP1B1, OATP1B3, OCT1, OAT2, OAT3, OCTN1, or OCTN2. Efflux and inhibition experiments were conducted in cells transfected with human ABCB1, ABCG2, ABCC2, or ABCC4. In vivo pharmacokinetic studies were done in knockout mice lacking Abcb1-type transporters.


RESULTS
Intracellular uptake was not appreciably affected by any of the studied solute carriers and was minute relative to the respective prototypical substrates. Sorafenib and sunitinib showed concentration-dependent (1 and 10 micromol/L), low to moderate affinity for ABCB1 but were not affected by the other ABC transporters. Both agents inhibited all tested ABC transporters. The absence of Abcb1 had no affect on plasma pharmacokinetics, but brain penetration was moderately increased by 1.9- and 2.9-fold for sorafenib and sunitinib, respectively, in knockout animals versus controls.


CONCLUSIONS
Unlike other tyrosine kinase inhibitors, sorafenib and sunitinib do not appear to rely on active transport to enter the cell nor are they high-affinity substrates for ABC efflux transporters. Based on these characteristics, these two drugs may be less susceptible to transporter-mediated alterations in systemic exposure and transporter-related resistance mechanisms.
Hu
Shuiying
S
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Chen
Zhaoyuan
Z
Franke
Ryan
R
Orwick
Shelley
S
Zhao
Ming
M
Rudek
Michelle A
MA
Sparreboom
Alex
A
Baker
Sharyn D
SD
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001557:Benzenesulfonates / Q000378:metabolism* / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007211:Indoles / Q000378:metabolism* / Q000493:pharmacokinetics; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D011725:Pyridines / Q000378:metabolism* / Q000493:pharmacokinetics; D011758:Pyrroles / Q000378:metabolism* / Q000493:pharmacokinetics; D000077157:Sorafenib; D000077210:Sunitinib; D013552:Swine; D014982:Xenopus laevis
C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; D001557:Benzenesulfonates; D002352:Carrier Proteins; D007211:Indoles; D000089762:Multidrug Resistance-Associated Protein 2; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000251:Adenosine Triphosphatases; D000077210:Sunitinib