Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel.

Article Details

Citation

Copy to clipboard

Smith NF, Acharya MR, Desai N, Figg WD, Sparreboom A

Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel.

Cancer Biol Ther. 2005 Aug;4(8):815-8.

PubMed ID

16210916 [ View in PubMed

]

Abstract

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 microM), 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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Paclitaxel	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Substrate	Details