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

Anne-Joy M de Graan; Cynthia S Lancaster; Amanda Obaidat; Bruno Hagenbuch; Laure Elens; Lena E Friberg; Peter de Bruijn; Shuiying Hu; Alice A Gibson; Gitte H Bruun; Thomas J Corydon; Torben S Mikkelsen; Aisha L Walker; Guoqing Du; Walter J Loos; Ron H N van Schaik; Sharyn D Baker; Ron H J Mathijssen; Alex Sparreboom

doi:10.1158/1078-0432.CCR-12-0761

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

Anne-Joy M de Graan, Cynthia S Lancaster, Amanda Obaidat, Bruno Hagenbuch, Laure Elens, Lena E Friberg, Peter de Bruijn, Shuiying Hu, Alice A Gibson, Gitte H Bruun, Thomas J Corydon, Torben S Mikkelsen, Aisha L Walker, Guoqing Du, Walter J Loos, Ron H N van Schaik, Sharyn D Baker, Ron H J Mathijssen, Alex Sparreboom^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	4433-4440
Number of pages	8
Journal	Clinical Cancer Research
Volume	18
Issue number	16
DOIs	https://doi.org/10.1158/1078-0432.CCR-12-0761
Publication status	Published - 15 Aug 2012

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10.1158/1078-0432.CCR-12-0761

http://hdl.handle.net/1765/67022

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de Graan, A.-J. M., Lancaster, C. S., Obaidat, A., Hagenbuch, B., Elens, L., Friberg, L. E., de Bruijn, P., Hu, S., Gibson, A. A., Bruun, G. H., Corydon, T. J., Mikkelsen, T. S., Walker, A. L., Du, G., Loos, W. J., van Schaik, R. H. N., Baker, S. D., Mathijssen, R. H. J., & Sparreboom, A. (2012). Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel. Clinical Cancer Research, 18(16), 4433-4440. https://doi.org/10.1158/1078-0432.CCR-12-0761

@article{0975f9e308ba4abd9ac9e3486e8adf80,

title = "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.",

author = "{de Graan}, {Anne-Joy M} and Lancaster, {Cynthia S} and Amanda Obaidat and Bruno Hagenbuch and Laure Elens and Friberg, {Lena E} and {de Bruijn}, Peter and Shuiying Hu and Gibson, {Alice A} and Bruun, {Gitte H} and Corydon, {Thomas J} and Mikkelsen, {Torben S} and Walker, {Aisha L} and Guoqing Du and Loos, {Walter J} and {van Schaik}, {Ron H N} and Baker, {Sharyn D} and Mathijssen, {Ron H J} and Alex Sparreboom",

year = "2012",

month = aug,

day = "15",

doi = "10.1158/1078-0432.CCR-12-0761",

language = "English",

volume = "18",

pages = "4433--4440",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "16",

}

de Graan, A-JM, Lancaster, CS, Obaidat, A, Hagenbuch, B, Elens, L, Friberg, LE, de Bruijn, P, Hu, S, Gibson, AA, Bruun, GH, Corydon, TJ, Mikkelsen, TS, Walker, AL, Du, G, Loos, WJ, van Schaik, RHN, Baker, SD, Mathijssen, RHJ & Sparreboom, A 2012, 'Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel', Clinical Cancer Research, vol. 18, no. 16, pp. 4433-4440. https://doi.org/10.1158/1078-0432.CCR-12-0761

TY - JOUR

T1 - Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel

AU - de Graan, Anne-Joy M

AU - Lancaster, Cynthia S

AU - Obaidat, Amanda

AU - Hagenbuch, Bruno

AU - Elens, Laure

AU - Friberg, Lena E

AU - de Bruijn, Peter

AU - Hu, Shuiying

AU - Gibson, Alice A

AU - Bruun, Gitte H

AU - Corydon, Thomas J

AU - Mikkelsen, Torben S

AU - Walker, Aisha L

AU - Du, Guoqing

AU - Loos, Walter J

AU - van Schaik, Ron H N

AU - Baker, Sharyn D

AU - Mathijssen, Ron H J

AU - Sparreboom, Alex

PY - 2012/8/15

Y1 - 2012/8/15

N2 - 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.

AB - 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.

U2 - 10.1158/1078-0432.CCR-12-0761

DO - 10.1158/1078-0432.CCR-12-0761

M3 - Article

C2 - 22711709

SN - 1078-0432

VL - 18

SP - 4433

EP - 4440

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 16

ER -

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

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