Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics

Abstract

Hydroxyurea is currently the only FDA-approved drug that ameliorates the pathophysiology of sickle cell anemia. Unfortunately, substantial interpatient variability in the pharmacokinetics (PK) of hydroxyurea may result in variation of the drug's efficacy. However, little is known about mechanisms that modulate hydroxyurea PK. Recent in vitro studies identifying hydroxyurea as a substrate for organic anion transporting polypeptide (OATP1B) transporters prompted the current investigation assessing the role of OATP1B transporters in modulating hydroxyurea PK. Using wild-type and Oatp1b knockout (Oatp1b(-/-)) mice, hydroxyurea PK was analyzed in vivo by measuring [(14)C]hydroxyurea distribution in plasma, kidney, liver, urine, or the exhaled (14)CO2 metabolite. Plasma levels were significantly reduced by 20% in Oatp1b(-/-) mice compared with wild-type (area under the curve of 38.64 or 48.45 μg·h(-1)·ml(-1), respectively) after oral administration, whereas no difference was observed between groups following intravenous administration. Accumulation in the kidney was significantly decreased by twofold in Oatp1b(-/-) mice (356.9 vs. 748.1 pmol/g), which correlated with a significant decrease in urinary excretion. Hydroxyurea accumulation in the liver was also decreased (136.6 vs. 107.3 pmol/g in wild-type or Oatp1b(-/-) mice, respectively) correlating with a decrease in exhaled (14)CO2. These findings illustrate that deficiency of Oatp1b transporters alters the absorption, distribution, and elimination of hydroxyurea thus providing the first in vivo evidence that cell membrane transporters may play a significant role in modulating hydroxyurea PK. Future studies to investigate other transporters and their role in hydroxyurea disposition are warranted for understanding the sources of variation in hydroxyurea's PK.

Influence of Drug Formulation on OATP1B-Mediated Transport of Paclitaxel

“…The significant reduction of paclitaxel administered without a solubilizer in the kidneys of Oatp1b2(−/−) mice at 5 min after drug administration is possibly the result of low expression of Oatp1b2 in renal cells of mice (35), and a similar phenotype has been reported previously for the Oatp1b2 substrate, hydroxyurea (36). The concentrations of paclitaxel in the intestine were not dependent on Oatp1b2 genotype at the early time point, where appearance of the drug likely reflects direct intestinal secretion (37).…”

Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia

“…Interpersonal variation was observed in the absorption time of HU in both younger and older children. This variation has been reported and may be due to variations in transmembrane transporters . Between liquid and capsule formulations, the largest difference in the PK profiles was a trend toward a shorter time to peak concentration following ingestion of the liquid compared with the capsule, but that difference did not reach statistical significance (0.74 versus 0.97 hours, P = 0.14; Table ).…”

“…This variation has been reported 17 and may be due to variations in transmembrane transporters. 25 Between liquid and capsule formulations, the largest difference in the PK profiles was a trend toward a shorter time to peak concentration following ingestion of the liquid compared with the capsule, but that difference did not reach statistical significance (0.74 versus 0.97 hours, P ¼ 0.14; Table 2). Pediatric PK data for HU are limited to 3 studies: observations from the internal pilot study (consisting of the first 22 participants) of the NIH-sponsored BABY HUG trial, 16 a study of children with SCA administered an oral tablet formulation, 18 and children receiving a first-dose of HU via a liquid suspension 17 (Table 4).…”

Sustained enhancement of OCTN1 transporter expression in association with hydroxyurea induced γ-globin expression in erythroid progenitors

“…They include 3 organic anion transporting polypeptides (OATP), 2 organic cation/carnitine transporters (OCTN) and 2 urea transporters (UT) [5]. Transporters of the OATP family are found predominantly in the liver, intestine, and kidneys and modulate the pharmacokinetics of HU [6]. Among HU transporters, only two, UTB and OCTN1, are highly expressed in bone marrow and in erythrocytes [7, 8].…”