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Pilot study of rosiglitazone as an in vivo probe of paclitaxel exposure
Author(s) -
Hertz Daniel L.,
Walko Christine M.,
Bridges Arlene S.,
Hull J. Heyward,
Herendeen Jill,
Rollins Kristan,
Watkins Paul B.,
Dees E. Claire
Publication year - 2012
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2012.04165.x
Subject(s) - rosiglitazone , paclitaxel , pharmacology , in vivo , dosing , medicine , cyp2c8 , pharmacokinetics , drug , cyp3a4 , chemotherapy , biology , cytochrome p450 , metabolism , receptor , microbiology and biotechnology
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Paclitaxel and rosiglitazone are primarily metabolized by CYP2C8 and their in vitro metabolism by human liver microsomes is correlated. Probe assays that quantify the in vivo activity of CYP enzymes which are important in drug metabolism have been developed for use in clinical pharmacology research. A probe of CYP2C8 that is easy to administer and interpret may be valuable for individualized dosing of paclitaxel. WHAT THIS STUDY ADDS • This pilot study demonstrates for the first time that there is an in vivo correlation between paclitaxel and rosiglitazone exposure. The finding, that a single rosiglitazone plasma concentration after oral dosing may explain significant variance in paclitaxel exposure, suggests that rosiglitazone may satisfy the requirements of a clinically useful in vivo probe. However, it is acknowledged that there is a need for further studies evaluating the use of rosiglitazone as a CYP2C8 probe and quantifying the relationship, in order to guide dosing of narrow therapeutic index drugs metabolized primarily by CYP2C8, such as paclitaxel. AIMS To evaluate the use of rosiglitazone and the erythromycin breath test (ERMBT), as probes of CYP2C8 and CYP3A4, respectively, to explain inter‐individual variability in paclitaxel exposure. METHODS The concentration of rosiglitazone at 3 h and ERMBT results were included in a regression model to explain the variability in paclitaxel exposure in 14 subjects. RESULTS Rosiglitazone concentration was significantly correlated with paclitaxel exposure ( P = 0.018) while ERMBT had no predictive value ( P = 0.47). CONCLUSIONS The correlation between the exposure of rosiglitazone and paclitaxel likely reflects mutual dependence on the activity of CYP2C8. Rosiglitazone or similar agents may have value as in vivo probes of CYP2C8 activity.