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Factors Affecting the In Vivo Lactone Stability and Systemic Clearance of the Lipophilic Camptothecin Analogue AR-67

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ABSTRACT

Purpose

The narrow efficacy-toxicity window of anticancer agents necessitates understanding of factors contributing to their disposition. This is especially true for camptothecins as they exist in the lactone and carboxylate forms with each moiety differentially interacting with efflux or uptake transporters. Here we determined the disposition of the lactone and carboxylate forms of AR-67, a 3rd generation camptothecin analogue.

Methods

Pharmacokinetic studies were conducted in rats given intravenous boluses of AR-67 lactone or carboxylate with or without pharmacologic inhibitor pretreatment (GF120918 or rifampin). Pharmacokinetic modeling was used to estimate clearances, while simulations assessed the impact of clearance changes on overall AR-67 exposure.

Results

Our modeling showed that carboxylate clearance was 3.5-fold higher than that of the lactone. GF120918 decreased lactone clearance only, but rifampin decreased both lactone and carboxylate clearances. Simulations showed that decreasing carboxylate clearance, which controls the overall drug disposition, leads to significant increase in AR-67 exposure.

Conclusion

The apparent in vivo blood stability of AR-67 is partly dependent on the increased carboxylate clearance. This may have clinical implications for populations with single nucleotide polymorphisms that impair the function of uptake transporter genes (e.g., SLCO1B1), which are potentially responsible for AR-67 carboxylate clearance.

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Abbreviations

AUC:

area under the plasma concentration versus time curve

BCRP/bcrp:

breast cancer resistance protein

OATP/Oatp:

organic anion transporting polypeptide

P-gp:

p-glycoprotein

USP:

United States Pharmacopeia

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ACKNOWLEDGMENTS

This work was supported in part by the National Institutes of Health (RCA123867A) and research grants from Arno Therapeutics.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, 40536, USA

    Eyob D. Adane, Zhiwei Liu, Tian-Xiang Xiang, Bradley D. Anderson & Markos Leggas

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  1. Eyob D. Adane
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  2. Zhiwei Liu
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  3. Tian-Xiang Xiang
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  4. Bradley D. Anderson
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  5. Markos Leggas
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Correspondence to Markos Leggas.

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Adane, E.D., Liu, Z., Xiang, TX. et al. Factors Affecting the In Vivo Lactone Stability and Systemic Clearance of the Lipophilic Camptothecin Analogue AR-67. Pharm Res 27, 1416–1425 (2010). https://doi.org/10.1007/s11095-010-0137-3

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  • DOI: https://doi.org/10.1007/s11095-010-0137-3

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