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Preclinical pharmacokinetics and bioavailability of noscapine, a tubulin-binding anticancer agent

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Abstract

Background

Noscapine, a naturally occurring antitussive phthalideisoquinoline alkaloid, is a tubulin-binding agent currently in Phase I/II clinical trials for anticancer therapy. Unlike currently available antimitotics such as taxanes and vincas, noscapine is water-soluble, well tolerated, and shows no detectable toxicity.

Objective

The goal was to develop a simple, sensitive, quantitative, selective, and less time-consuming high-performance liquid chromatography (HPLC) method for determination of noscapine and to study its pharmacokinetics in mice models.

Method

Noscapine was extracted from mice plasma using the protein-precipitation method and detected using a reversed-phase C8 column with mobile phase consisting of 35% acetonitrile and 65% ammonium acetate buffer (pH 4.5) at 232 nm wavelength. Pharmacokinetic studies of noscapine were performed in mice following intravenous bolus at 10 mg/kg and oral administrations at 75, 150, and 300 mg/kg.

Results

The standard curves for noscapine estimation were linear between 390 and 50,000 ng/ml (lower limit of quantification was 390 ng/ml) and the recovery was ∼80%. Following 10 mg/kg intravenous dose, mean plasma concentrations of 7.88 μg/ml were achieved at 5 min in mice and declined with undetectable levels at 4 h. The mean total body clearance was 4.78 l/h. The mean volume of distribution (V d) was 5.05 l. Non-compartmental analysis yielded the mean area under the plasma concentration–time curve (AUC) for noscapine as 53.42, 64.08, and 198.35 h μg/ml reaching maximum plasma concentrations (C max) of 12.74, 23.24, and 46.73 μg/ml at a t max of 1.12, 1.50, and 0.46 h at the linearly increasing dose levels.

Conclusion

A rapid and simple HPLC/UV method for the quantification of noscapine in plasma has been developed to study pharmacokinetics of noscapine at tumor-suppressive doses in the mouse. Since orally available anticancer drugs are rare, therefore, noscapine, an innocuous agent, having a mean oral bioavailability of 31.5% over the studied dose range merits its further advancement in humans for anticancer therapy.

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Acknowledgments

We thank the Technical Support Unit at Lupin Research Park for their assistance in animal maintenance, dosing, and sample collection. We thank members of the Joshi Laboratory for discussions. This work was supported by a grant to HCJ from the National Institutes of Health.

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Authors and Affiliations

  1. Laboratory for Drug Discovery and Research, Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA

    Ritu Aneja & Harish C. Joshi

  2. BR Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India

    Neerupma Dhiman & Ramesh Chandra

  3. Preclinical Pharmacokinetics and Metabolism Laboratories, Lupin Research Park, Pune, 411042, India

    Jyoti Idnani, Anshumali Awasthi & Sudershan K. Arora

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  1. Ritu Aneja
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  2. Neerupma Dhiman
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Correspondence to Ritu Aneja.

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Aneja, R., Dhiman, N., Idnani, J. et al. Preclinical pharmacokinetics and bioavailability of noscapine, a tubulin-binding anticancer agent. Cancer Chemother Pharmacol 60, 831–839 (2007). https://doi.org/10.1007/s00280-007-0430-y

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  • DOI: https://doi.org/10.1007/s00280-007-0430-y

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