Short-term distribution of nicotine in the rat lung

doi:10.1016/j.drugalcdep.2004.02.011

Drug and Alcohol Dependence

Volume 75, Issue 2, 16 August 2004, Pages 193-198

https://doi.org/10.1016/j.drugalcdep.2004.02.011 Get rights and content

Abstract

Nicotine is a dibasic amine with a pK_a of 8.0. At physiological pH roughly 1/4 of the compound is nonionized and able to cross membranes, most notably the alveolar membranes of the lung. Many models of nicotine addiction assume that the time it takes nicotine to pass from inspired air to the blood stream is negligible, resulting in a large peak or bolus in nicotine blood levels following each puff from a cigarette. However, the results of several previous studies have suggested that the lung may act as a short-term depot for nicotine. This was directly investigated in the present study. In anesthetized rats with open-chest and ventilated lungs, 0.4 mg [ $^{3} H$ ]nicotine in 50 μl was rapidly injected into the right ventricle of the heart and blood was sampled from the left ventricle. It was found that the [ $^{3} H$ ]nicotine left the lungs at a significantly slower rate than [ $^{14} C$ ]dextran, a compound which remains in the plasma compartment (3.11% versus 7.71% injected/s for [ $^{3} H$ ]nicotine and [ $^{14} C$ ]dextran, respectively). In similar experiments, lung, heart and brain tissue were obtained at 5 s intervals. Significant [ $^{3} H$ ]nicotine remained in the lung throughout the 40 s period, with lung tissue nicotine greater than brain at all time points. These results indicate that the lung may act as a short-term depot for nicotine, delaying and depressing its appearance in the systemic arterial circulation.

Introduction

It has been recognized for centuries that the smoking of tobacco is difficult to cease once the practice has begun. With nicotine being the major alkaloid in tobacco and having significant biological activity, it has long been realized that nicotine plays a major role in the dependence of tobacco smoking (Surgeon General’s Report, 1988, NIDA Research Report, 1998). Nicotine’s unique physical properties allow it to be inhaled and rapidly enter the body via the lung. It is a weak base containing a pyridine and pyrrolidine ring, each possessing a tertiary amine. The pK_a of the pyridine nitrogen is 3.22, whereas the pK_a of the pyrrolidine nitrogen is 7.92 at physiological temperature and ionic strength (Banyasz, 1999). With these characteristics, approximately 23% of nicotine is nonionized at physiological pH and available to rapidly cross biological membranes. Instantaneously, as some of the nonionized nicotine leaves the alveolar fluid, an equal amount of the ionized nicotine loses a proton to become uncharged to maintain the approximate 3:1 ratio of charged to uncharged nicotine. Thus, essentially all of the nicotine is available to cross the lung membrane into the blood.

Nicotine is absorbed from smoke into the lung relatively quickly primarily because of the large alveolar surface area and the large blood perfusion of the pulmonary capillary beds (Benowitz, 1990). This rapid transfer across the lung and into the blood has been suggested to account for the higher dependence potential of inhaled nicotine compared to the transdermal, oral, nasal, or buccal routes. It is widely accepted that the transit time of nicotine from lung to brain is on the order of 7–10 s (NIDA Research Report, 1998). Further, the rapid rate of nicotine transfer through the lungs is thought to result in the appearance of a transient large peak in nicotine blood levels a few seconds after each inhaled puff (Armitage et al., 1968, Armitage and Turner, 1970). The arrival of this bolus of nicotine to the brain is thought to be important for the reinforcing effects of nicotine from cigarette smoking (Russell and Feyerabend, 1978, Benowitz, 1990). This “bolus effect” presumes that the transfer of nicotine across the alveoli is virtually instantaneous such that the peak arterial levels of nicotine would be higher, and the lag time between inhalation and entry into the brain shorter, than even after an intravenous injection (Benowitz, 1990).

Since the lung is the major route of nicotine absorption for smokers, its very large lipophilic surface area, however, might actually impede the transfer of nicotine into the blood stream. Radiological studies show an accumulation of intravenous [ $^{14} C$ ]nicotine in lung tissue at steady state (Waddell and Marlowe, 1976) suggesting that the lung can act as a depot for nicotine. Rose et al. (1999) made the first determinations of the appearance of nicotine in arterial blood at short time intervals (5 s) following both smoking and the intravenous administration of nicotine in humans. The results of their study showed that the peak arterial plasma concentrations of nicotine were far lower than would have been predicted for inhaled tobacco smoke according to the bolus hypothesis. The peak measured levels were roughly 7 ng/ml versus a predicted value of 100 ng/ml. The explanation proposed for this low arterial nicotine concentration was that nicotine initially distributes into lung tissue, slowing its entry into the arterial circulation.

The purpose of the present study was to directly measure the disposition of nicotine in lung tissue over short time periods and assess the validity of the explanation proposed by Rose et al. To accomplish this, [ $^{3} H$ ]nicotine was rapidly injected into the right ventricle of rats and the appearance of [ $^{3} H$ ]nicotine in left ventricular blood was determined at approximately 2 s intervals. In this way, the transit of nicotine through the pulmonary circulation was determined. In addition, lung, brain, and arterial blood samples were obtained in separate experiments and analyzed at various time points. These experiments thus characterize the impact of the lung on the passage of nicotine into the systemic arterial circulation as an approximation of the lung’s influence on nicotine kinetics following inhalation from smoking.

Section snippets

Chemicals

Radiolabeled (−)[N-methyl- $^{3} H$ ]nicotine and [carboxyl- $^{14} C$ ]dextran were purchased from Perkin-Elmer NEN (Boston, MA) and American Radiolabeled Chemicals (St. Louis, MO), respectively. The (−)nicotine tartrate was purchased from ICN Biomedicals Inc. (Aurora, OH) and all doses of nicotine were calculated based on the free-base form of the drug. Ketamine was obtained from Abbott Laboratories (North Chicago, IL), and xylazine was purchased from the Butler Company (Columbus, OH). Heparin was obtained

Kinetics of nicotine in the pulmonary circulation

In order to assess the characteristics of nicotine’s transit through the pulmonary circulation, a series of experiments was conducted to determine the rate of appearance of a known quantity of [ $^{3} H$ ]nicotine in the left ventricle of the heart after its rapid injection into the right ventricle. The characteristics of [ $^{3} H$ ]nicotine recovery were compared to that of [ $^{14} C$ ]dextran, a high molecular-weight compound which does not readily cross cellular membranes. Using the same protocol as the [ $^{3} H$

Discussion

The focus of this study was to investigate the short-term distribution of nicotine in lung tissue and measure the kinetics of its appearance in the systemic arterial blood following transit through the lung. A widely accepted model of nicotine kinetics posits that nicotine absorbed from cigarette smoke is almost instantaneously transferred to the blood and travels as a bolus to the brain and other organs within 5–10 s (Armitage and Turner, 1970, Russell and Feyerabend, 1978, Benowitz, 1992, NIDA

Acknowledgements

The authors are grateful to Dr. Harrell Hurst for advice and assistance in the analysis of nicotine kinetics. The study was supported by a grant from the National Institutes of Drug Abuse (DA07479).

References (12)

N.L Benowitz
Cigarette smoking and nicotine addiction
Med. Clin. North Am.
(1992)
J.E Rose et al.
Arterial nicotine kinetics during cigarette smoking and intravenous nicotine administration: implications for addiction
Drug Alcohol Depend.
(1999)
A.K Armitage et al.
Pharmacological basis for the tobacco smoking habit
Nature
(1968)
A.K Armitage et al.
Absorption of nicotine in cigarette and cigar smoke through the oral mucosa
Nature
(1970)
Banyasz, J.L., 1999. The physical chemistry of nicotine. In: Gorrod, J.W., Jacob, P. (Eds.), Analytical Determination...
Benowitz, N.L., 1990. Pharmacokinetic considerations in understanding nicotine dependence. In: Bock, G., Marsh, J....

There are more references available in the full text version of this article.

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Short-term distribution of nicotine in the rat lung

Abstract

Introduction

Section snippets

Chemicals

Kinetics of nicotine in the pulmonary circulation

Discussion

Acknowledgements

Med. Clin. North Am.

Drug Alcohol Depend.

Pharmacological basis for the tobacco smoking habit

Nature

Absorption of nicotine in cigarette and cigar smoke through the oral mucosa

Nature