Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel

• Published in: Clinical cancer research 2012-08, Vol.18 (16), p.4433-4440
• Main Authors: de Graan, Anne-Joy M, Lancaster, Cynthia S, Obaidat, Amanda, Hagenbuch, Bruno, Elens, Laure, Friberg, Lena E, de Bruijn, Peter, Hu, Shuiying, Gibson, Alice A, Bruun, Gitte H, Corydon, Thomas J, Mikkelsen, Torben S, Walker, Aisha L, Du, Guoqing, Loos, Walter J, van Schaik, Ron H N, Baker, Sharyn D, Mathijssen, Ron H J, Sparreboom, Alex
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animals; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacokinetics; Cell Line; Cricetinae; Female; Genotype; Hepatocytes - metabolism; Humans; Inactivation, Metabolic; Liver - metabolism; Male; Mice; Mice, Knockout; Middle Aged; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Organic Anion Transporters - deficiency; Organic Anion Transporters - genetics; Organic Anion Transporters, Sodium-Independent - genetics; Polymorphism, Genetic; Solute Carrier Organic Anion Transporter Family Member 1b1; Solute Carrier Organic Anion Transporter Family Member 1B3; Taxoids - metabolism; Taxoids - pharmacokinetics
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-0761

Docetaxel is extensively metabolized by CYP3A4 in the liver but mechanisms by which the drug is taken up into hepatocytes remain poorly understood. We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3 and (ii) inherited genetic defects in this process may impair systemic drug elimination. Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1*1A (wild-type), OATP1B1*5 [c.521T>C (V174A); rs4149056], OATP1B3, or the mouse transporter Oatp1b2. Docetaxel clearance was evaluated in wild-type and Oatp1b2-knockout mice as well as in two cohorts of patients with multiple variant transporter genotypes (n = 213). Docetaxel was found to be a substrate for OATP1B1, OATP1B3, and Oatp1b2 but was not transported by OATP1B1*5. Deficiency of Oatp1b2 in mice was associated with an 18-fold decrease in docetaxel clearance (P = 0.0099), which was unrelated to changes in intrinsic metabolic capacity in mouse liver microsomes. In patients, however, none of the studied common reduced function variants in OATP1B1 or OATP1B3 were associated with docetaxel clearance (P > 0.05). The existence of at least two potentially redundant uptake transporters in the human liver with similar affinity for docetaxel supports the possibility that functional defects in both of these proteins may be required to confer substantially altered disposition phenotypes. In view of the established exposure-toxicity relationships for docetaxel, we suggest that caution is warranted if docetaxel has to be administered together with agents that potently inhibit both OATP1B1 and OATP1B3.