title: Noscapine recirculates enterohepatically and induces self-clearance.
abstract: Noscapine (Nos), an antitussive benzylisoquinoline opium alkaloid, is a non-toxic tubulin-binding agent currently in Phase II clinical trials for cancer chemotherapy. While preclinical studies have established its tumor-inhibitory properties in various cancers, poor absorptivity and rapid first-pass metabolism producing several uncharacterized metabolites for efficacy, present an impediment in translating its efficacy in humans. Here we report novel formulations of Nos in combination with dietary agents like capsaicin (Cap), piperine (Pip), eugenol (Eu) and curcumin (Cur) known for modulating Phase I and II drug metabolizing enzymes. In vivo pharmacokinetic (PK), organ toxicity evaluation of combinations, microsomal stability and in vitro cytochrome P450 (CYP) inhibition effects of Nos, Cap and Pip using human liver microsomes were performed. Single-dose PK screening of combinations revealed that the relative exposure of Nos (2 μg h/mL) was enhanced by 2-fold (4 μg h/mL) by Cap and Pip and their plasma concentration-time profiles showed multiple peaking phenomena for Nos indicating enterohepatic recirculation or differential absorption from intestine. CYP inhibition studies confirmed that Nos, Cap and Pip are not potent CYP inhibitors (IC50>1 μM). Repeated oral dosing of Nos, Nos+Cap and Nos+Pip showed lower exposure (Cmax and AUClast) of Nos on day 7 compared to day 1. Nos Cmax decreased from 3087 ng/mL to 684 ng/mL and AUClast from 1024 ng h/mL to 508 ng h/mL. In presence of Cap and Pip, the decrease in Cmax and AUClast of Nos was similar. This may be due to potential enzyme induction leading to rapid clearance of Nos as the trend was observed in Nos alone group also. The lack of effect on intrinsic clearance of Nos suggests that the potential drug biotransformation modulators employed in this study did not contribute toward increased exposure of Nos on repeated dosing. We envision that Nos-induced enzyme induction could alter the therapeutic efficacy of co-administered drugs, hence emphasizing the need for strategic evaluation of the metabolism of Nos to reap its maximum efficacy.
authors.affiliation: Advinus Therapeutics Limited, Karnataka 560058, India; Manipal University, Manipal, Karnataka 576104, India.
authors.forename: Rao
authors.initials: R
authors.lastname: Mukkavilli
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, United States.
authors.forename: Sushma R
authors.initials: SR
authors.lastname: Gundala
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, United States.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yang
authors.affiliation: Advinus Therapeutics Limited, Karnataka 560058, India.
authors.forename: Gajanan R
authors.initials: GR
authors.lastname: Jadhav
authors.affiliation: Advinus Therapeutics Limited, Karnataka 560058, India.
authors.forename: Subrahmanyam
authors.initials: S
authors.lastname: Vangala
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Reid
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, United States. Electronic address: raneja@gsu.edu.
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
mesh_terms: D000818:Animals; D000996:Antitussive Agents / Q000493:pharmacokinetics*; D018565:Food-Drug Interactions; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D009665:Noscapine / Q000493:pharmacokinetics*
chemical_list: D000996:Antitussive Agents; D009665:Noscapine
keywords: CYP inhibition; LC/MS/MS; Liver microsomes; Noscapine