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Prediction of human pharmacokinetics and tissue distribution of apicidin, a potent histone deacetylase inhibitor, by physiologically based pharmacokinetic modeling

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Abstract

Purpose

The objectives of this study were to develop physiologically based models for the pharmacokinetics (PK) and organ distribution of apicidin in rats and mice and to predict human PK in blood and organs.

Methods

The PK of apicidin was characterized in rats and mice after i.v. bolus injection, and distribution to various tissues was determined in rats following i.v. infusions at steady state. The developed models were prospectively validated within rat and within mouse and by scaling from rat to mouse using data after multiple i.v. injections. Human PK was predicted by the physiologically based modeling using intrinsic clearance data for humans from in vitro experiments.

Results

The Cls predicted for human (9.8 ml/min/kg) was lower than those found in mice (116.9 ml/min/kg) and rats (61.6 ml/min/kg), and the Vss predicted for human (1.9 l/kg) was less than in mice (2.0 l/kg) and rats (2.5 l/kg). Consequently, the predicted t 1/2 was longer in human (2.3 h) than in mice and rats (0.4 and 0.9 h, respectively). The highest concentrations of apicidin were predicted in liver followed by adipose tissue, kidney, lung, spleen, heart, arterial blood, venous blood, small intestine, stomach, muscle, testis, and brain.

Conclusions

The developed models adequately described the PK of apicidin in rats and mice and were applied to predict human PK. These models may be useful in predicting human blood and tissue concentrations of apicidin under different exposure conditions.

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Acknowledgments

This work was supported in part by the National Research Foundation (NRF) grant (2009-0083962) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2010-0022780).

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Authors and Affiliations

  1. College of Pharmacy, Catholic University of Daegu, Gyeongsan-si, Gyeongbuk, Korea

    Beom Soo Shin

  2. Ordway Research Institute, Albany, NY, USA

    Jürgen B. Bulitta

  3. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA

    Joseph P. Balthasar

  4. School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon, Gyeonggi-do, 440-746, Korea

    Minki Kim, Yohan Choi & Sun Dong Yoo

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  1. Beom Soo Shin
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  2. Jürgen B. Bulitta
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  3. Joseph P. Balthasar
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  4. Minki Kim
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  5. Yohan Choi
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  6. Sun Dong Yoo
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Corresponding author

Correspondence to Sun Dong Yoo.

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Shin, B.S., Bulitta, J.B., Balthasar, J.P. et al. Prediction of human pharmacokinetics and tissue distribution of apicidin, a potent histone deacetylase inhibitor, by physiologically based pharmacokinetic modeling. Cancer Chemother Pharmacol 68, 465–475 (2011). https://doi.org/10.1007/s00280-010-1502-y

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  • DOI: https://doi.org/10.1007/s00280-010-1502-y

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