Apparent tolerance to the acute effect of nicotine results in part from distribution kinetics.

Abstract

Persons exposed to nicotine develop tolerance to many of its effects. When heart rate and forearm venous blood concentration are plotted against time after intravenous administration of nicotine, a greater increase in heart rate is seen for-a given nicotine concentration during the rising phase of nicotine. concentrations than during the decreasing phase. This could be due to acute tolerance or to more rapid distribution of drug to effect site (brain) than to venous blood. To distinguish between these possibilities, six rabbits were given nicotine intravenously. Blood samples were taken from the internal jugular vein (reflecting brain concentration), and the femoral vein and artery. Brain concentrations peaked before femoral venous concentrations. Seven men received intravenous infusions of nicotine. Peripheral venous blood concentrations and cardiovascular responses were measured. Heart rate peaked before venous concentrations. A physiological kinetic model, fit to the rabbit data, was scaled to humans and used to predict "brain" concentrations in them. Heart rate and predicted brain concentrations peaked simultaneously. We conclude that the rapid development of tolerance to the cardioaccelerating effect of nicotine can be attributed, at least in part, to its distribution kinetics.

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

“…After oral dosage, plots of mephedrone effect versus observed plasma mephedrone concentrations revealed a clockwise hysteresis loop in both oral dosages. A clockwise hysteresis loop has been described after cathinone (Schechter 1990) or MDMA administration (Hysek et al 2012) and could be attributable to the more rapid distribution of the drug to the brain than to venous blood (Porchet et al 1987). …”

A noninvasive method for delivering controlled doses of nicotine via cigarette smoke

“…The extremely rapid absorption of nicotine from cigarette smoke in the lungs permits variations in the rate of distribution of nicotine from blood into body organs to affect nicotine levels measured shortly after the dosing procedure (Porchet, Benowitz, & Sheiner, 1987). For example, in the study by Feyerabend et al (1985), nicotine levels were measured within 2 min of a rapid (l-min) injection, and plasma nicotine increments showed CVs of 61 % for the first injection.…”

Metabolism and Disposition Kinetics of Nicotine

“…The rapid rate of delivery of nicotine by smoking (or intravenous injection, which presents similar distribution kinetics) results in high levels of nicotine in the central nervous system with little time for development of tolerance. The result is a more intense pharmacologic action (Porchet et al, 1987). The short time interval between puffing and nicotine entering the brain also allows the smoker to titrate the dose of nicotine to a desired pharmacologic effect, further reinforcing drug self-administration and facilitating the development of addiction.…”