TY - JOUR
T1 - Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel
AU - Smith, Nicola F.
AU - Acharya, Milin R.
AU - Desai, Neil
AU - Figg, William D.
AU - Sparreboom, Alex
PY - 2005/8
Y1 - 2005/8
N2 - 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 μM), 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.
AB - 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 μM), 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.
KW - Docetaxel
KW - Hepatic uptake
KW - OATP1B3
KW - Paclitaxel
KW - Taxanes
UR - http://www.scopus.com/inward/record.url?scp=25144491657&partnerID=8YFLogxK
U2 - 10.4161/cbt.4.8.1867
DO - 10.4161/cbt.4.8.1867
M3 - Article
C2 - 16210916
AN - SCOPUS:25144491657
SN - 1538-4047
VL - 4
SP - 815
EP - 818
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 8
ER -