title: P-glycoprotein does not actively transport nicotine and cotinine.
abstract: The ABCB1 gene transporter P-glycoprotein (P-gp) exists in the blood-brain barrier (BBB) and placenta and limits many drugs passing through the BBB and placenta. Several recent studies have raised confounding results regarding the roles of P-gp in nicotine disposition. To ascertain this question, we examined the effects of nicotine and its major oxidative metabolite, cotinine, on ATPase activity using P-gp containing membranes, in which nicotine and cotinine-stimulated inorganic Pi was used as a marker of the binding affinity of nicotine and cotinine to P-gp. At concentrations ranging from 5 to 1000 microm, both nicotine and cotinine produced modest stimulative effects on ATPase activity in the P-gp containing membrane. The Clint values of nicotine and cotinine were 0.01 and 0.007 minute(-1) x 10(-3), respectively. The positive control, verapamil, at concentrations ranging from 1 to 100 microm, created apparent stimulative effects on ATPase activity, with a Clint value of 1.7 minute(-1) x 10(-3), consistent with previously reported results. The results of the current study suggest that nicotine and cotinine were not actively transported by P-gp out of the cells. The observed carrier-mediated nicotine transport in various cell lines may be mediated by other transporter proteins but not P-gp.
authors.affiliation: Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina 49425, USA.
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Wang
authors.forename: John S
authors.initials: JS
authors.lastname: Markowitz
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Donovan
authors.forename: C Lindsay
authors.initials: CL
authors.lastname: Devane
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D001693:Biological Transport, Active; D001812:Blood-Brain Barrier / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D003367:Cotinine / Q000378:metabolism*; D006801:Humans; D009538:Nicotine / Q000378:metabolism*; D014700:Verapamil / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009538:Nicotine; D014700:Verapamil; D000251:Adenosine Triphosphatases; D003367:Cotinine