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Noscapine recirculates enterohepatically and induces self-clearance
Rao Mukkavilli1, Sushma R Gundala2, Chunhua Yang2
1Advinus Therapeutics Limited, Karnataka 560058, India; Manipal University, Manipal, Karnataka 576104, India.
Summary
Noscapine (Nos) efficacy in cancer is limited by poor absorption. Combining Nos with dietary agents like capsaicin and piperine enhanced its initial exposure but led to reduced levels upon repeated dosing, suggesting enzyme induction.
Area of Science:
- Pharmacology
- Drug Metabolism
- Cancer Chemotherapy
Background:
- Noscapine (Nos) is an antitussive alkaloid with demonstrated anti-cancer properties.
- Poor bioavailability and rapid metabolism hinder Noscapine's clinical efficacy.
- Dietary agents may modulate drug-metabolizing enzymes to improve Noscapine's therapeutic potential.
Purpose of the Study:
- To evaluate novel formulations of Noscapine with dietary agents (capsaicin, piperine, eugenol, curcumin).
- To assess the pharmacokinetic and safety profiles of these combinations.
- To investigate the in vitro effects of Noscapine and its combinations on cytochrome P450 enzymes.
Main Methods:
- In vivo pharmacokinetic studies and organ toxicity evaluations.
- In vitro microsomal stability assays.
- In vitro cytochrome P450 inhibition assays using human liver microsomes.
Main Results:
- Single-dose administration of Noscapine with capsaicin or piperine doubled Noscapine exposure.
- Plasma concentration-time profiles indicated enterohepatic recirculation or differential absorption.
- Noscapine, capsaicin, and piperine were not potent CYP inhibitors (IC50 > 1 μM).
- Repeated dosing of Noscapine alone or with capsaicin/piperine resulted in decreased exposure, suggesting enzyme induction.
Conclusions:
- Dietary agents can initially enhance Noscapine exposure but may lead to reduced levels with repeated dosing due to enzyme induction.
- Noscapine itself may induce enzymes, potentially affecting co-administered drugs.
- Strategic evaluation of Noscapine metabolism is crucial for optimizing its therapeutic efficacy.