Pharmacokinetics of freebase nicotine and nicotine salts following subcutaneous administration in male rats

Abstract

Nicotine lactate, nicotine tartrate, nicotine benzoate, and freebase nicotine (FBN) are four forms of nicotine salt systems that are present in tobacco products. However, few in vivo studies have compared their pharmacological (pK) efficacies, which are important for understanding their roles in the addiction and abuse of tobacco and nicotine products. In this work, the pK of the above nicotine salt systems was studied by subcutaneously injecting their aqueous solutions in rats and obtaining blood samples from the jugular vein. Nicotine levels in the blood were analyzed by LC–MS/MS. The results demonstrated that rapid nicotine absorption occurred in all nicotine systems. Of them, NB had the smallest Tmax, while FBN had the largest Tmax. The nicotine metabolic rate and clearance decreased for FBN, indicating that nicotine retention in the body was higher than for the other three salt‐based systems. Compared with nicotine salts, FBN could reach and maintain a higher concentration in the animal model. Additionally, as the benzoic acid ratios increased, the Cmax of the nicotine benzoate (NB) in the plasma decreased. This indicates that the lower the pH, the lower the Cmax. When different concentrations of NB were used, the higher the NB concentration, the greater the Cmax and AUC(0‐t). These results demonstrate that nicotine adsorption by NB in the animal model depended on both pH and concentration. This baseline information could be used to explain different clinical pharmacological observations in humans, though this study only considered the effects of nicotine on pharmacokinetics in vivo.

Electronic Vaporization of Nicotine Salt or Freebase produces differential effects on metabolism, neuronal activity and behavior in male and female C57BL/6J mice

“…Preclinical studies on the effect of formulation on metabolism are contradictory. One study conducted in rats found that following a single sub-cutaneous dose of nicotine freebase, serum nicotine levels were higher than those in rats injected with nicotine salts [ 6 ], which are consistent with the results of the current study. However, in another study, mice exposed to nicotine salt vapor had significantly higher serum cotinine levels than mice exposed to nicotine freebase.…”

“…When studying the physiological, metabolic and behavioral effects of drugs of abuse it is imperative to take into consideration sex differences as well as delivery methods [ 6 , 8 ]. Previous preclinical studies have noted a difference in nicotine and cotinine serum levels in male and female mice exposed to nicotine, with males showing higher nicotine serum levels than females [ 7 , 8 ].…”

“…Potential physiological differences between nicotine formulations remain unclear, as there are few studies that investigate the pharmacokinetic effects of nicotine salt and freebase in preclinical models. It has been previously shown in rats that a single subcutaneous injection of nicotine freebase reached and maintained higher serum nicotine levels than a single injection of nicotine salt [ 6 ]. Using an e-vape self administration paradigm, Henderson and Cooper et al [ 7 ], found that mice exposed to nicotine salt sought more nicotine deliveries than their free-base counterparts.…”

The science behind vaping

“…This is the first study to highlight the possibility of a toxicological impact of increased aerosolization resulting from polydrug consumption through e‐cigarettes. In another study dealing with nicotine delivery, this time of an in vivo nature, Han et al 6 consider the importance of the form of nicotine (which is dependent on pH). In the tobacco leaf, nicotine exists in its salt form, and when it is extracted and purified to create pharmaceutical grade nicotine, it converts to its unprotonated or ‘freebase’ form.…”

“…In the tobacco leaf, nicotine exists in its salt form, and when it is extracted and purified to create pharmaceutical grade nicotine, it converts to its unprotonated or ‘freebase’ form. Han et al 6 examine the pharmacokinetics of freebase nicotine compared with three salts (nicotine lactate, nicotine tartrate and nicotine benzoate). Following subcutaneous administration in rats, the authors found that freebase nicotine can reach higher blood concentrations and nicotine concentrations were sensitive to the pH of the preparations.…”