Bioavailability Of Nicotine Research Articles

In vitro characteristics of nicotine microspheres for transnasal delivery

A new transnasal formulation containing nicotine was developed and characterized. Sephadex® G25 and G50, crosslinked dextran microspheres, were loaded with nicotine base (NB) and nicotine hydrogenotartrate (NHT). Their high swelling capacity, which is believed to enhance the bioavailability of nicotine by acting on the nasal mucosa, was not altered by the loading process. The in vitro kinetics were measured by the means of a special diffusion chamber which mimics the hydration conditions of the nasal cavity. 90% of the nicotine were released in a time similar to the nasal residence time (15 min). The delivery from a regular nasal device is described and related to the porosity of the microspheres.

Bioassay‐driven analysis of chewing tobacco extracts

AbstractThe aims were to develop a method to simulate extraction of toxic components into human saliva, to identify these components through bioassay‐driven analyses using the Microtox® test, and to quantify the toxic compounds. Chewing tobacco extractions into artificial saliva simulated oral chewing conditions. The Microtox bioassay‐directed subfractionation scheme identified acutely toxic components in chewing tobacco extracts. GC‐MS identified and quantified the toxic components. The subfractionation (pH 7 extraction, pH 2 extraction, then pH 10 extraction using organic solvents) scheme was shown to be comparable to biological digestive sequences and to simulate nicotine bioavailability. The low toxicity of artificial saliva allowed development of a sensitive bioassay. Nicotine was the major acutely toxic agent detected. Classification by Draize ocular irritative categories showed that leached nicotine concentrations were mildly to moderately irritating. Thus, the Microtox test can be used to detect irritative compounds and subfractions, and can be potentially applied to saliva biological monitoring in humans.

Absolute bioavailability of nicotine applied to different nasal regions

The absolute bioavailability of nicotine administered nasally, as drops to the nasal conchae and nasal septum, and as a nasal spray, has been studied in eight healthy volunteers. Single nasal doses of 1 mg nicotine were given and plasma concentrations of nicotine were followed for 6 h. Compared to an intravenous infusion of nicotine, the bioavailability of the nasal administrations was 60 to 75%. The rate of absorption was fast, the maximum concentration being reached after about 10 min. In the present study, there was no significant difference in the rate or extent of absorption between the different nasal treatments.

Stable isotope studies of nicotine kinetics and bioavailability

The stable isotope-labeled compound 3',3'-dideuteronicotine was used to investigate the disposition kinetics of nicotine in smokers, the systemic absorption of nicotine from cigarette smoke, and the bioavailability of nicotine ingested as oral capsules. Blood levels of labeled nicotine could be measured for 9 hours after a 30-minute intravenous infusion. Analysis of disposition kinetics in 10 healthy men revealed a multiexponential decline after the end of an infusion, with an elimination half-life averaging 203 minutes. This half-life was longer than that previously reported, indicating the presence of a shallow elimination phase. Plasma clearance averaged 14.6 ml/min/kg. The average intake of nicotine per cigarette was 2.29 mg. A cigarette smoke-monitoring system that directly measured particulate matter in smoke was evaluated in these subjects. Total particulate matter, number of puffs on the cigarette, total puff volume, and time of puffing correlated with the intake of nicotine from smoking. The oral bioavailability of nicotine averaged 44%. This bioavailability is higher than expected based on the systemic clearance of nicotine and suggests that there may be significant extrahepatic metabolism of nicotine.

Failure of behavioral dependence induction and oral nicotine bioavailability in rats.

As failure to induce behavioral dependence to oral nicotine (0.31 mM) might be caused by taste aversion. Sixteen rats were presented nicotine around the taste aversion threshold (0.025 mM then 0.05 mM) as only source of fluid for 10 weeks. Eight of them had undergone portacaval anastomosis (PCA) to increase bioavailability of nicotine by preventing liver first-pass. Weekly choice sessions between nicotine and water demonstrated neither aversion nor preference for nicotine. In 10 control and 11 PCA rats accustomed to drink 0.31 mM nicotine, plasma nicotine was determined after 3 ml/kg intragastric nicotine-solution. In both groups, 0.05 mM nicotine did not lead to detectable levels but 0.31 mM nicotine led to peak levels higher than seen in man after smoking. Similar levels were recorded after spontaneous nicotine drinking in 8 isolated and 18 grouped normal rats accustomed to 0.31 mM nicotine. Drinking nicotine for at least 10 weeks did not induce behavioral dependence in these rats. This cannot be explained by poor nicotine bioavailability by oral route.

Recent studies of nicotine metabolism in humans.

Recent studies of quantitative and qualitative aspects of nicotine metabolism, and the use of metabolic data for estimating nicotine intake in humans are discussed. Previously reported methodology for determining nicotine bioavailability has been improved by using stable isotope-labeled nicotine administered intravenously. Combined gas chromatography-mass spectrometry with selected ion monitoring has been used to simultaneously determine concentrations of isotopically-labeled nicotine and tobacco-derived nicotine in blood. Nicotine intake from cigarette smoking was estimated from clearance of labeled nicotine and blood concentrations of tobacco-derived nicotine. Progress in elucidating the metabolic profile of nicotine in humans, and the use of nicotine metabolites as markers of tobacco smoke consumption is summarized.

Clinical pharmacokinetics of nicotine

Nicotine intake is considered to be a major factor in sustaining tobacco addiction. For this reason, nicotine gum has recently been introduced as an adjuvant to smoking cessation. The introduction of nicotine as a 'therapeutic' entity necessitates a careful examination of its clinical pharmacokinetics. Insufficient data exist to quantitatively assess the absorption of nicotine after oral administration. Based upon physicochemical and pharmacokinetic principles, the oral bioavailability of nicotine would be expected to be less than 20%. The limited data available in the literature appear to support this conclusion. Absorption from the oral mucosa is the principal site of nicotine absorption in subjects who chew tobacco or nicotine gum. Absorption by this route is highly pH dependent. Nicotine is also readily absorbed from the nasal mucosa, and after topical administration. Nicotine distributes extensively into body tissues with a volume of distribution ranging from 1.0 to 3.0 L/kg. Nicotine has been shown to transfer across the placenta and into breast milk in humans. Plasma protein binding is negligible, ranging from 4.9 to 20%. The predominant route of nicotine elimination is hepatic metabolism. Although a number of metabolites of nicotine have been identified, it is unclear whether any of these compounds contribute to the pharmacological effect of nicotine. Nicotine is also excreted unchanged in urine in a pH-dependent fashion. With urinary pH less than 5, an average 23% of the nicotine dose is excreted unchanged. When urinary pH is maintained above 7.0, unchanged nicotine urinary excretion drops to 2%. After intravenous administration, nicotine exhibits biexponential decline in plasma. Total plasma clearance ranges from 0.92 to 2.43 L/min. During urinary acidification, renal clearance averages 0.20 L/min. Non-renal blood clearance averages 1.2 L/min, indicating that nicotine elimination is dependent on hepatic blood flow. The literature is devoid of information regarding the effect of disease on the pharmacokinetics of nicotine. Based upon the drug's pharmacokinetics in healthy smokers, it would be anticipated that disease states which alter hepatic blood flow may have the greatest impact on nicotine pharmacokinetics. In addition, drugs which alter hepatic blood flow may cause significant alterations in the systemic clearance of nicotine. Dependence on smoking appears to be related, at least in part, to the achievement of a rapid rise in plasma nicotine concentrations. If this assessment is correct, the most desirable adjuvant for smoking cessation would be one that closely mimics this pattern of plasma nicotine concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical pharmacokinetics of nicotine.

Nicotine intake is considered to be a major factor in sustaining tobacco addiction. For this reason, nicotine gum has recently been introduced as an adjuvant to smoking cessation. The introduction of nicotine as a 'therapeutic' entity necessitates a careful examination of its clinical pharmacokinetics. Insufficient data exist to quantitatively assess the absorption of nicotine after oral administration. Based upon physicochemical and pharmacokinetic principles, the oral bioavailability of nicotine would be expected to be less than 20%. The limited data available in the literature appear to support this conclusion. Absorption from the oral mucosa is the principal site of nicotine absorption in subjects who chew tobacco or nicotine gum. Absorption by this route is highly pH dependent. Nicotine is also readily absorbed from the nasal mucosa, and after topical administration. Nicotine distributes extensively into body tissues with a volume of distribution ranging from 1.0 to 3.0 L/kg. Nicotine has been shown to transfer across the placenta and into breast milk in humans. Plasma protein binding is negligible, ranging from 4.9 to 20%. The predominant route of nicotine elimination is hepatic metabolism. Although a number of metabolites of nicotine have been identified, it is unclear whether any of these compounds contribute to the pharmacological effect of nicotine. Nicotine is also excreted unchanged in urine in a pH-dependent fashion. With urinary pH less than 5, an average 23% of the nicotine dose is excreted unchanged. When urinary pH is maintained above 7.0, unchanged nicotine urinary excretion drops to 2%. After intravenous administration, nicotine exhibits biexponential decline in plasma. Total plasma clearance ranges from 0.92 to 2.43 L/min. During urinary acidification, renal clearance averages 0.20 L/min. Non-renal blood clearance averages 1.2 L/min, indicating that nicotine elimination is dependent on hepatic blood flow. The literature is devoid of information regarding the effect of disease on the pharmacokinetics of nicotine. Based upon the drug's pharmacokinetics in healthy smokers, it would be anticipated that disease states which alter hepatic blood flow may have the greatest impact on nicotine pharmacokinetics. In addition, drugs which alter hepatic blood flow may cause significant alterations in the systemic clearance of nicotine. Dependence on smoking appears to be related, at least in part, to the achievement of a rapid rise in plasma nicotine concentrations. If this assessment is correct, the most desirable adjuvant for smoking cessation would be one that closely mimics this pattern of plasma nicotine concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)