Population Pharmacokinetics of Nicotine and Its Metabolites I. Model Development

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-d2, 2 mg), and COT (COT-d4, 10 mg) simultaneously. Frequent plasma/saliva samples were taken for measurement of concentrations of NIC-d2, COT-d2, 3HC-d2, COT-d4, and 3HC-d4. 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 t1/2 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-d2 in the blood was modeled as a time delay (t1/2 = 12 min) in its release from the liver following NIC-d2 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.