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

Aneja, Ritu; Dhiman, Neerupma; Idnani, Jyoti; Awasthi, Anshumali; Arora, Sudershan K.; Chandra, Ramesh; Joshi, Harish C.

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. 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. 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. 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. 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.

PHARMACOKINETICS; TUBULINS; ANTINEOPLASTIC agents; BIOCHEMISTRY; CHEMICAL kinetics; HYDROGEN-ion concentration

Cancer Chemotherapy & Pharmacology, 2007, Vol 60, Issue 6, p831

0344-5704

Academic Journal

10.1007/s00280-007-0430-y