Chronopharmacokinetics of nicotine.
BACKGROUND
For high-clearance drugs such as nicotine, hemodynamic changes throughout the day may be expected to influence the rate of metabolism.


METHODS
To assess the effects of meals and diurnal rhythms on nicotine clearance, an intravenous infusion of nicotine bitartrate was administered for 48 hours to 11 subjects. Two models to determine nicotine clearance variation throughout the day are described. Both models were used to estimate the mean effect of meal and diurnal rhythms on nicotine clearance and individual parameters that were regressed against baseline covariates. Clearance was modeled as a function of time [CL(t)] and split it in three components: a (constant) baseline value (theta 1), its circadian (diurnal) variation, and the effect of meal: CL(t) = [theta 1 + circadian(t)] [1 + meal(t)]. A two-compartmental (time-variant) model incorporating CL(t) was then fitted to the data providing estimates of CL(t) conditional on literature values of the time-invariant parameters (volume of distribution and intercompartmental clearances).


RESULTS
The estimated circadian(t) showed a maximum at approximately 11 AM and a flat minimum from 6 PM to 3 AM; the estimated meal(t) showed a sharp increase up to 1 hour (after the meal), at which point clearance is increased 42%, and a slower decrease thereafter, returning to baseline (zero) after 2.8 hours. Individual estimates of baseline clearance are found to have a linear relationship with body weight. No other covariate, sex in particular, effect could be found.
Gries
J M
JM
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco 94143-0446, USA.
Benowitz
N
N
Verotta
D
D
D000328:Adult; D002849:Chromatography, Gas; D002940:Circadian Rhythm; D004435:Eating; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009538:Nicotine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D018722:Nicotinic Agonists; D009538:Nicotine