The acute effects of daily nicotine intake on heart rate – A toxicokinetic and toxicodynamic modelling study

Abstract

Joint physiologically-based toxicokinetic and toxicodynamic (PBTK/TD) modelling was applied to simulate concentration-time profiles of nicotine, a well-known stimulant, in the human body following single and repeated dosing. Both kinetic and dynamic models were first calibrated by using in vivo literature data for the Caucasian population. The models were then used to estimate the blood and liver concentrations of nicotine in terms of the Area Under Curve (AUC) and the peak concentration (Cmax) for selected exposure scenarios based on inhalation (cigarette smoking), oral intake (nicotine lozenges) and dermal absorption (nicotine patches). The model simulations indicated that whereas frequent cigarette smoking gives rise to high AUC and Cmax in blood, the use of nicotine-rich dermal patches leads to high AUC and Cmax in the liver. Venous blood concentrations were used to estimate one of the most common acute effects, mean heart rate, both at rest and during exercise. These estimations showed that cigarette smoking causes a high peak heart rate, whereas dermal absorption causes a high mean heart rate over 48h. This study illustrates the potential of using PBTK/TD modelling in the safety assessment of nicotine-containing products.

A simple physiologically based pharmacokinetic model evaluating the effect of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans

“…Similar to existing studies, it was assumed that simple mass action kinetics and flow-limited tissue distributions could accurately predict nicotine and cotinine systemic distribution (Plowchalk et al, 1992; Teeguarden et al, 2013; Gajewska et al, 2014). Model design was inspired by previous works used to predict nicotine and cotinine pharmacokinetics and pharmacodynamics in both rats and humans, with the most notable works being those of Plowchalk et al (1992) and Teeguarden et al (2013).…”

“…Complexity of PBPK models varies greatly between individual studies, as their design is based upon the complexity of output variables and the desired scale and accuracy of model predictions. Many pharmacokinetic and toxicokinetic models of nicotine and cotinine disposition kinetics have been proposed in literature (Gabrielsson and Bondesson, 1987; Plowchalk et al, 1992; Robinson et al, 1992; Schwartz et al, 1993; Yamazaki et al, 2010; Teeguarden et al, 2013; Gajewska et al, 2014). However, to date there have been no models constructed that evaluate the effect of anti-nicotine antibodies on nicotine disposition in the blood and in the brain.…”

Modeling of Physiology Based Toxico-Kinetics and Toxico-Dynamic to Diagnose Acute Effects of Nicotine on Heart Rate

“…Addition of a compliance chamber reduces pulse wave reflection and normalizes ventricular function. The pulmonary replacement with the lowresistance artificial lung is tolerated by the right ventricular in this short term model [8]. Matching the impedance of an artificial lung for pulmonary replacement to native pulmonary impedance is important in preventing right ventricular dysfunction.…”

“…Where: These parameters values [13][14][15][16][17][18] are mentioned in Gajewska M et al [8] and Loizou et al [16] which are discussed in the references. The volume of the organ is calculated with the information of organ's weight and its density which are tabulated in Table 2.…”

“…The standard values of kidney parameters are mentioned by Gajewska M et al [8,19]. Thus from the above information the modeling of kidney is done and the amount of changes in blood concentration for each organ is evaluated, based on the value of nicotine dosage given into our body, the amount of nicotine that can be distributed to the organ can be estimated (Table 4).…”