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Brief Communication
Identification of OATP1B3 as a High-Affinity Hepatocellular Transporter of Paclitaxel
Nicola F. Smith, Milin R. Acharya, Neil Desai, William D. Figg and Alex Sparreboom
volume 4 | issue 8
august 2005Pages: 815-818
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Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response is extensive, and largely unexplained. We hypothesized that this is due to affinity of taxanes for an uptake transporter that indirectly regulates elimination pathways. Here, we studied accumulation of [3H]docetaxel and [3H]paclitaxel in Xenopus laevis oocytes injected with cRNA of the liver-specific organic anion transporting polypeptide (OATP) family members OATP1B1 (OATP2) or OATP1B3 (OATP8). Taxane transport by OATP1B1 expressing oocytes was not significantly different from that by water-injected controls, whereas uptake by OATP1B3 was 2.2-fold higher for docetaxel (P=0.0007) and 3.3-fold higher for paclitaxel (P<0.0001). OATP1B3-mediated paclitaxel transport was saturable (Michaelis-Menten constant, 6.79 ?M), time-dependent, and highly sensitive to chemical inhibition. Paclitaxel uptake was not inhibited by ketoconazole or tariquidar. However, uptake was inhibited by the formulation excipient Cremophor (74.4% inhibition, P<0.0001), cyclosporin A (25.2%, P=0.005), glycyrrhizic acid (24.6%, P=0.012), and hyperforin (28.4%, P=0.003). Consistent with this finding, Cremophor was found to significantly affect the hepatic uptake of paclitaxel in mice. These data suggest that OATP1B3 is a key regulator of hepatic uptake, and may therefore play a role in the variable response to treatment with taxanes.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.