Preclinical drug metabolism and pharmacokinetics of salinomycin, a potential candidate for targeting human cancer stem cells.
There has been a search for new anticancer agents to treat cancer resistance throughout the globe. Salinomycin (SAL), a broad spectrum antibiotic and a coccidiostat has been found to counter tumour resistance and kill cancer stem cells with better efficacy than the existing chemotherapeutic agents; paclitaxel and doxorubicin. This refocused its importance for treatment of human cancers. In this study, we studied the in vitro drug metabolism and pharmacokinetic parameters of SAL. SAL undergoes rapid metabolism in liver microsomes and has a high intrinsic clearance. SAL metabolism is mainly mediated by CYP enzymes; CYP3A4 the major enzyme metabolising SAL. The percent plasma protein binding of SAL in human was significantly lower as compared to mouse and rat plasma. CYP inhibition was carried out by chemical inhibition and recombinant enzyme studies. SAL was found to be a moderate inhibitor of CYP2D6 as well as CYP3A4. As CYP3A4 was the major enzyme responsible for metabolism of SAL, in vivo pharmacokinetic study in rats was done to check the effect of concomitant administration of Ketoconazole (KTC) on SAL pharmacokinetics. KTC, being a selective CYP3A4 inhibitor increased the systemic exposure of SAL significantly to 7-fold in AUC0-α and 3-fold increase in Cmax of SAL in rats with concomitant KTC administration.
Department of Pharmacology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India.
Kahkashan
K
Resham
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India.
Prinesh N
PN
Patel
Department of Pharmacology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India.
Dinesh
D
Thummuri
Department of Pharmacology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India.
Lalita
L
Guntuku
Department of Pharmacokinetics and Metabolism, Daiichi Sankyo India Pharma Pvt Ltd, Village Sarhaul, Sector 18, UdyogVihar Industrial Area, Gurgaon, 122015, Haryana, India.
Vanya
V
Shah
Department of Pharmacokinetics and Metabolism, Daiichi Sankyo India Pharma Pvt Ltd, Village Sarhaul, Sector 18, UdyogVihar Industrial Area, Gurgaon, 122015, Haryana, India.
Ramesh B
RB
Bambal
Department of Pharmacology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, 500037, Telangana, India. Electronic address: vgmnaidu@niperhyd.ac.in.
V G M
VG
Naidu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011714:Pyrans / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000095662:Polyether Polyketides
D000970:Antineoplastic Agents; D011714:Pyrans; C010327:salinomycin; D000095662:Polyether Polyketides
CYP; Drug metabolism; In vitro metabolism; In vivo pharmacokinetics; Pharmacokinetics; Salinomycin