Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters.
OBJECTIVE
Hydroxyurea has proven laboratory and clinical therapeutic benefits for sickle cell anemia and other diseases, yet many questions remain about its in vivo pharmacokinetic and pharmacodynamic profiles. Previous reports suggest that hydroxyurea passively diffuses across cells, but its observed rapid absorption and distribution are more consistent with facilitated or active transport. We investigated the potential role of solute carrier (SLC) transporters in cellular uptake and accumulation of hydroxyurea.


METHODS
Passive diffusion of hydroxyurea across cell membranes was determined using the parallel artificial membrane permeability assay. SLC transporter screens were conducted using in vitro intracellular drug accumulation and transcellular transport assays in cell lines and oocytes overexpressing SLC transporters. Gene expression of SLC transporters was measured by real-time polymerase chain reaction in human tissues and cell lines.


RESULTS
Hydroxyurea had minimal diffusion across a lipid bilayer but was a substrate for five different SLC transporters belonging to the organic cation/carnitine transporters and organic anion transporting polypeptides (OATP) families of transporters and urea transporters A and B. Further characterization of hydroxyurea transport revealed that cellular uptake by OATP1B3 is time- and temperature-dependent and inhibited by known substrates of OATP1B3. Urea transporters A and B are expressed differentially in human tissues and erythroid cells, and transport hydroxyurea bidirectionally via facilitated diffusion.


CONCLUSIONS
These studies provide new insight into drug transport proteins that may be involved in the in vivo absorption, cellular distribution, and elimination of hydroxyurea. Elucidation of hydroxyurea transcellular movement should improve our understanding of its pharmacokinetics and pharmacodynamics, and may help explain some of the interpatient drug variability observed in patients with sickle cell anemia.
Department of Hematology, St Jude Children's Research Hospital, Memphis, TN 38105, USA. aisha.walker@stjude.org
Aisha L
AL
Walker
Ryan M
RM
Franke
Alex
A
Sparreboom
Russell E
RE
Ware
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics; D018938:Caco-2 Cells; D002460:Cell Line; D002463:Cell Membrane Permeability; D005260:Female; D044950:Flavanones / Q000494:pharmacology; D015870:Gene Expression; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D006918:Hydroxyurea / Q000378:metabolism* / Q000493:pharmacokinetics*; D020014:K562 Cells; D008051:Lipid Bilayers / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013696:Temperature; D013997:Time Factors; D057900:Transcytosis / Q000187:drug effects; D014162:Transfection; D014982:Xenopus laevis
D000970:Antineoplastic Agents; D044950:Flavanones; D008051:Lipid Bilayers; D026901:Membrane Transport Proteins; D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C005274:naringin; D006918:Hydroxyurea
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