Dataset Information

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

ABSTRACT:

Purpose

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.

Experimental design

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).

Results

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).

Conclusions

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.

SUBMITTER: de Graan AJ

PROVIDER: S-EPMC3464009 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Publications

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

de Graan Anne-Joy M AJ Lancaster Cynthia S CS Obaidat Amanda A Hagenbuch Bruno B Elens Laure L Friberg Lena E LE de Bruijn Peter P Hu Shuiying S Gibson Alice A AA Bruun Gitte H GH Corydon Thomas J TJ Mikkelsen Torben S TS Walker Aisha L AL Du Guoqing G Loos Walter J WJ van Schaik Ron H N RH Baker Sharyn D SD Mathijssen Ron H J RH Sparreboom Alex A

Clinical cancer research : an official journal of the American Association for Cancer Research 20120618 16

<h4>Purpose</h4>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.<h4>Experimental design</h4>Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1*1 ...[more]

PMID: 22711709

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Dataset Information

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

Purpose

Experimental design

Results

Conclusions

Publications

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

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