title: Population pharmacokinetics of nicotine and its metabolites I. Model development.
abstract: We present a mechanistic population model for the pharmacokinetics of nicotine (NIC), its primary (CYP2A6-generated) metabolite cotinine (COT), and COT's primary (CYP2A6-generated) metabolite, trans-3'-hydroxycotinine (3HC). Sixty-six subjects received oral deuterium-labeled NIC (NIC-d(2), 2 mg), and COT (COT-d(4), 10 mg) simultaneously. Frequent plasma/saliva samples were taken for measurement of concentrations of NIC-d(2), COT-d(2), 3HC-d(2), COT-d(4), and 3HC-d(4). A mechanistic population pharmacokinetic model was fitted to all data simultaneously. Most of the pharmacokinetic parameters found here agree with previous studies and with a previous model-independent analysis of these data. However, 3HC t(1/2) was found to be considerably shorter than a previously reported value, possibly because 3HC elimination was saturated with the larger doses used in the previous study. Additionally, the delay in the appearance of COT-d(2) in the blood was modeled as a time delay (t(1/2) = 12 min) in its release from the liver following NIC-d(2) administration. The most important result of the previous model-independent analysis of these data, confirmed here, is that NIC clearance to COT and the 3HC:COT saliva concentration ratio are highly correlated (r = 0.7-0.8). The correlation above support that idea that the 3HC:COT ratio can be used as a predictor of CYP2A6 activity and nicotine clearance. The model-based analysis extends and further justifies this conclusion.
authors.affiliation: Division of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, University of California, San Francisco, San Francisco General Hospital Medical Center, San Francisco, CA 94143-1220, USA.
authors.forename: Micha
authors.initials: M
authors.lastname: Levi
authors.forename: Delia A
authors.initials: DA
authors.lastname: Dempsey
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Sheiner
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001682:Biological Availability; D001711:Biotransformation; D003367:Cotinine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D065637:Cytochrome P-450 CYP2A6; D003903:Deuterium; D005260:Female; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008954:Models, Biological; D015233:Models, Statistical; D009538:Nicotine / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011159:Population Surveillance; D011237:Predictive Value of Tests; D012016:Reference Values; D012463:Saliva / Q000378:metabolism
chemical_list: D018722:Nicotinic Agonists; C001381:hydroxycotinine; D009538:Nicotine; D003903:Deuterium; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D003367:Cotinine