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In vitro–in vivo extrapolation of CYP2C8-catalyzed paclitaxel 6α-hydroxylation: effects of albumin on in vitro kinetic parameters and assessment of interindividual variability in predicted clearance

  • Pharmacokinetics and Disposition
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European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objectives

This study aimed to characterize the effects of bovine serum albumin (BSA) on the kinetics of CYP2C8-catalyzed paclitaxel 6α-hydroxylation in vitro; determine whether the addition of BSA to incubations improves the prediction of paclitaxel hepatic clearance via this pathway in vivo; and assess interindividual variability in predicted clearance.

Methods

The kinetics of paclitaxel 6α-hydroxlation by human liver microsomes (HLM) and recombinant CYP2C8 were characterized in incubations performed with and without BSA (2% w/v) supplementation, and the in vitro kinetic data were extrapolated to provide estimates of in vivo clearances. The Simcyp population-based ADME simulator was used to determine interindividual variability in the predicted clearances.

Results

Supplementation of incubations of HLM with BSA resulted in a 3.6-fold increase in the microsomal intrinsic clearance for paclitaxel 6α-hydroxylation, due mainly to a reduction in Km (7.08 ± 2.50 to 2.26 ± 0.39 μM), while addition of BSA to incubations of recombinant CYP2C8 resulted in an approximate doubling of intrinsic clearance. Mean values of predicted in vivo hepatic clearance were in good agreement with clinical data when in vitro data obtained in the presence of BSA were used for IV-IVE. Simcyp predicted 20- to 30-fold interindividual variability in in vivo paclitaxel hepatic clearance via the 6α-hydroxylation pathway.

Conclusions

Human liver microsomal Km and intrinsic clearance values are over- and underpredicted, respectively, when incubations of the CYP2C8 substrate paclitaxel are performed without BSA supplementation. IV-IVE based on kinetic parameters generated in the presence of BSA improves the accuracy of predicted paclitaxel hepatic clearance.

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Acknowledgments

This study was supported by grants from the National Health and Medical Research Council of Australia, the Thailand Research Fund, and the Faculty of Medicine, Khon Kaen University, Thailand. Financial support from the Thailand Research Fund through the Royal Golden Ph.D. Program (PHD/0167/2548) to Nitsupa Wattanachai and Wichittra Tassaneeyakul is acknowledged. Assistance from David J. Elliot in establishing the paclitaxel 6α-hydroxylation assay and performing the binding experiments is gratefully acknowledged.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

    Nitsupa Wattanachai & Wichittra Tassaneeyakul

  2. Department of Clinical Pharmacology, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, 5042, Australia

    Nitsupa Wattanachai, Thomas M. Polasek, Tahlia M. Heath & John O. Miners

  3. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia

    Tahlia M. Heath

  4. Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand

    Verawan Uchaipichat & Wongwiwat Tassaneeyakul

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  1. Nitsupa Wattanachai
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  2. Thomas M. Polasek
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Correspondence to John O. Miners.

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Wattanachai, N., Polasek, T.M., Heath, T.M. et al. In vitro–in vivo extrapolation of CYP2C8-catalyzed paclitaxel 6α-hydroxylation: effects of albumin on in vitro kinetic parameters and assessment of interindividual variability in predicted clearance. Eur J Clin Pharmacol 67, 815–824 (2011). https://doi.org/10.1007/s00228-011-1001-z

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