Organic Anion Transporting Polypeptide 1B (OATP1B) Transporters Modulate Hydroxyurea Pharmacokinetics

• Published in: Blood 2012-11, Vol.120 (21), p.1008-1008
• Main Authors: Walker, Aisha L., Lancaster, Cynthia S, Ware, Russell E., Sparreboom, Alex
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V120.21.1008.1008

Abstract 1008 Sickle cell is the most common inherited blood disorder affecting millions worldwide. Hydroxyurea is currently the only FDA approved drug for the treatment of sickle cell anemia (SCA) that alters disease pathophysiology. Known for inducing fetal hemoglobin production, hydroxyurea can decrease hospitalizations, vaso-occlusive pain episodes, and mortality associated with SCA. Although efficacious for many patients, a large degree of inter-patient variability in pharmacokinetic (PK) and pharmacodynamic (PD) properties of hydroxyurea has been noted, but sources of this variation remain largely undefined. Plasma transmembrane transporters have been shown to play an important role in the determination drug PK and PD of various xenobiotics. Our recent in vitro studies have demonstrated that hydroxyurea is a substrate for specific solute carrier (SLC) transporters including members of the organic anion transporting polypeptide 1B (OATP1B) subfamily which consists of OATP1B1, and OATP1B3 in humans, and one mouse orthologue Oatp1b2. These transporters are highly expressed on the sinusoidal membrane of hepatocytes, and function as uptake transporters bringing substrates from the blood into the liver. Limited reports have suggested that Oatp1b2 transcript is also found in kidney and intestine as well. In the present study we evaluated the uptake of the hydroxyurea by different haplotypes of hOATP1B3 transporter in vitro, as well as the influence of the Oatp1b2 transporter on hydroxyurea PK in vivo using a transporter knock-out mouse model. Transporter-mediated cellular uptake of hydroxyurea was determined in vitro by measuring [14C]-hydroxyurea accumulation in Xenopus laevis oocytes that over express two common haplotypes of OATP1B3. hOATP1B3*1 and the functional variant hOATP1B3*2 that contains the 334T>G and 699G>A SNPs were assessed. In vivo PK Studies were performed using a knockout model mouse model in which mOATP1b2 was eliminated from the DBA/LcaJ1 background. Mice were dose with 50mg/kg of [14C]-hydroxyurea via oral gavage or intravenous (i.v.) injection. Serial blood samples were collected at defined timepoints and concluded with terminal blood and tissue collections at 2 hours post injection. Hydroxyurea levels were determined based on radioactivity in plasma and liver, and kidney homogenate. Accumulation in the urine was also measured over a 3 day period. In vitro kinetic studies did not show any differences between OATP1B3*1 and OATP1B3*2 hap