Review Article

Oinical Pharmacokinetics 12: 30-40 (1987) 0312-5963/87/000 1-00301$05. 5010

© ADIS Press Limited All rights reserved.

Clinical Pharmacokinetics of Nicotine Craig K. Svensson Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit

Summary

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. Absorptionjrom 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. Thus, the slow rise in plasma concentrations after chewing nicotine gum may suggest a pharmacokinetic explanation for the relatively high failure rate with this method of smoking cessation. It appears that because the rate of nicotine absorption is even slower than with the gum formulation, transdermal preparations are unlikely to be a satisfactory alternative to smoking. Further investigations are, therefore,

Pharmacokinetics of Nicotine

31

required to determine a formulation which gives the desired plasma nicotine concentration profile. One of the major effects of smoking on drug therapy is the induction of drug-metabolising enzymes. However, the effects on drug metabolising capacity when a subject changes from smoking to nicotine gum has not yet been studied. The effect nicotine itself has on drug metabolism in humans is also unknown. Considerable work remains to define adequately the clinical pharmacokinetics of nicotine. Determination offactors which influence the efficacy of nicotine as an adjuvant in smoking cessation may prove beneficial in reducing the number of tobacco consumers worldwide.

Tobacco use has resulted in major health problems worldwide. The 1983 United States Surgeon General's Report on Smoking and Health concluded that cigarette smoking is the largest avoidable cause of death and disability in the United States (Department of Health and Human Services 1983). Thus, extensive efforts at reducing the number of tobacco consumers have been launched by both governmental and private agencies. Chronic nicotine inhalation is considered to be a major factor in sustaining tobacco addiction (Russell & Feyerabend 1978). It is obvious, however, that there are also strong emotional and social attachments to the 'tobacco habit' (herein refered to as 'psychological dependence'). Thus, a smoker attempting to abstain may have to overcome both a psychological and physical dependence on tobacco, which immediately presents a formidable obstacle to many individuals. Recently, nicotine gum has been introduced as an adjuvant to smoking cessation, to help smokers overcome their psychological dependence while the physical dependence is maintained. Once the psychological dependence has been conquered, the use of nicotine gum is reduced and eventually withdrawn. Numerous studies suggest that this intervention may aid motivated individuals in 'kicking the habit' (Fee & Stewart 1982; Hjalmarson 1984; Hughes & Miller 1984; Jarvis et a1. 1982). In addition, the use of nicotine by alternate routes of administration (i.e. intranasal and transdermal) is currently under clinical investigation. The health consequences of nicotine consumption as a single entity have not been carefully examined. Assuming that, as with most agents, there is a relationship between nicotine concentration and

its pharmacological and toxicological effect, variability in the disposition of this compound may result in variability in the therapeutic response to nicotine used as an adjuvant to smoking cessation. Therefore, the present review summarises our knowledge to date on the clinical pharmacokinetics of nicotine, with special reference to the implications in its use as an adjuvant in smoking cessation.

1. Pharmacokinetic Properties of Nicotine 1.1 Absorption

1.1.1 Absorption from the Gastrointestinal Tract While not administered orally for therapeutic purposes, the gastrointestinal absorption of nicotine may be toxicologically important. Numerous cases have been reported in which tobacco products have been accidentally ingested by children (Malizia et a1. 1983). In addition, the use of tobacco enemas is a popular home remedy for constipation in some areas (Garcia-Estrada & Fischman 1977; Willis 1937). Based upon physicochemical and pharmacokinetic principles, nicotine would be expected to exhibit very low systemic availability after oral administration. Nicotine should exist as a diprotonated ion at pH values found in the stomach, while the monoprotonated form would predominate at the pH of the intestine. In addition, if the non-renal clearance of nicotine (see section 1.4) is assumed to approximate hepatic clearance, the firstpass extraction of nicotine would be extensive, resulting in only about 25 to 30% of the drug which is absorbed reaching the systemic circulation. Thus,

32

Pharmacokinetics of Nicotine

40

"C

~0

III

.c

«

•

30

•

20

"l10 0

I

5

•

••

•

•

I

I

I

6

7

8

9

Buffer pH Fig. 1. Effect of buffer pH on the buccal absorption of nicotine (adapted from Beckett et al. 1972).

under normal physiological conditions, the availability of nicotine after oral administration would be expected to be quite low. The limited data available in the literature appear to support these conclusions. For example, Travell (1940) found that the lethal dose of oral nicotine in cats with a stomach pH of 1.2 was more than 100 times that in cats with a stomach pH of 8.6. Beckett et al. (1972) observed a mean 14% urinary recovery of nicotine in normal subjects after oral administration and during urinary acidification. Russell and Feyerabend (1978) reported 1 subject who obtained 'smoking levels of plasma nicotine' following the oral ingestion of 28mg of nicotine base. In addition, 70% of cases of tobacco ingestion reported to the United States National Poison Center Network remain 'asymptomatic', indicating that significant systemic absorption of nicotine from tobacco ingestion does not occur in the majority of cases (Iserson 1983). It must be noted, however, that rectal administration of drugs may bypass the 'first-pass' effect; thereby resulting in substantial increases in the systemic availability of high extraction drugs such as nicotine (de Boer et al. 1982). The systemic exposure to nicotine following the administration of tobacco enemas may, therefore, be substantially greater than after oral ingestion. 1.1.2 Absorption/rom the Oral Mucosa Absorption of nicotine from the oral mucosa is the principal route of nicotine administration in

smokers who do not inhale, users of chewing tobacco and subjects using nicotine gum. Absorption by this route is highly dependent upon the pH of the surrounding medium (see fig. 1). The significance of these findings regarding the use of nicotine gum as an adjuvant in smoking cessation is discussed in sections 1.4.3 and 4. 1.1.3 Absorption from the Nasal Mucosa Snuffing (the inhalation of dried tobacco powder into the nasal cavity) has enjoyed a certain degree of popularity through the years, even to the point of the establishment of societies of snuff users (along with organised snuffing competitions) in some localities. Its use testifies to the probable significant absorption of nicotine through the nasal mucosa. Indeed, plasma nicotine concentrations in daily snuff users are similar to those seen in daily cigarette smokers (Russell et al. 1981). The observation that nicotine appears to be rapidly and efficiently absorbed after inhalation of snuff (Russell et al. 1980; Temple 1976) led to an examination of the potential use ofa nasal nicotine solution as an adjuvant in smoking cessation. Preliminary studies indicate that nicotine is absorbed by this route more rapidly than by the use of nicotine gum (Russell et al. 1983; West et al. 1984). There is, however, substantial intersubject variability in the plasma nicotine concentrations. Considerable work remains to determine the factors influencing the nasal absorption of nicotine. 1.1.4 Absorption from Topical Application It has long been appreciated that nicotine can be absorbed after topical administration. Faulkner (1933) reported the case of a florist who sat on a bench which was wet with a 40% nicotine solution and manifested symptoms of severe nicotine poisoning within 15 minutes. The subject was hospitalised and made an unremarkable recovery. Upon discharge, the patient dressed in the clothes he wore at the time of exposure (which had been stored in a paper bag during his hospitalisation). Apparently, the seat of his pants was still damp and within 1 hour he again manifested symptoms of nicotine poisoning.

Pharmacokinetics of Nicotine

Green tobacco sickness is an illness occurring in harvesters of tobacco believed to be secondary to percutaneous absorption of nicotine from contact with wet tobacco leaves (Gehlbach et a1. 1974). Indeed, increased urinary excretion of cotinine (the major metabolite of nicotine) has been shown to occur upon such contact (Gehlbach et al. 1979). These observations led to the suggestion that transdermal application of nicotine may provide an alternative adjuvant to smoking cessation for those individuals who have a personal aversion to nicotine gum. Data from 1 subject (Rose et al. 1984) indicate that nicotine is absorbed more slowly following transdermal administration (peak concentration obtained at 90 minutes) compared to nasal or buccal administration (peak within 10 and 40 minutes, respectively). Experiments in cats have demonstrated that the transdermal absorption of nicotine is also pH dependent (Travell 1960). 1.2 Distribution

1.2.1 Tissue Uptake Nicotine distributes extensively into body tissues with a volume of distribution 1 to 3 times bodyweight (see section 1.4). To the author's knowledge, the tissue distribution of nicotine in humans has not been studied. Animal studies indicate species differences in the distribution of nicotine to certain organs, particularly to the brain (Schmiterlow et a1. 1967; Stalhandske 1970; Tsujimoto et al. 1975), which make any attempt at interspecies extrapolations difficult. 1.2.2 Protein Binding Nicotine exhibits negligible binding to plasma proteins. Benowitz et al. (1982) found that the plasma protein binding of nicotine in humans averaged 4.9%, with no evidence of concentration or gender dependence. Other studies have demonstrated that binding may be as high as 20%, with albumin as the predominant binding protein (Schievelbein 1984).

33

1.2.3 Placental Transfer and Secretion into Breast Milk Nicotine readily crosses the placental 'barrier'. Umbilical vein serum nicotine concentrations at birth generally exceed maternal nicotine serum concentrations in smoking women (Luck & Nau 1984a). Amniotic fluid nicotine concentrations between the sixteenth and twenty-fourth week of gestation were also found to exceed maternal serum nicotine concentrations. Thus, exposure of the developing child to nicotine may be quite substantial. The significance of this exposure on the child's wellbeing are unknown at this time. It is clear, however, that tobacco smoking adversely affects pregnancy outcome. Smoking is associated with an increased incidence of spontaneous abortion, a decreased birthweight and an increased perinatal mortality (Abel 1984). Perinatal exposure to cigarette smoke has also been associated with behavioural changes in offspring (Abel 1984). The role of nicotine in these adverse effects is unknown. Nicotine has also been found to concentrate in breast milk. Milk : serum nicotine concentration ratio averaged 2.92 in a group of nursing smokers (Luck & Nau 1984b). Nursed infants' serum: maternal serum nicotine concentration ratio averaged 0.06 (Luck & Nau 1984a).

1.3 Elimination 1.3.1 Metabolism The predominant route of nicotine elimination is hepatic metabolism (Gorrod & Jenner 1975). A large number of metabolites of nicotine have been identified in mammalian species (Schievelbein 1984). Cotinine, a product of oxidation of the pyrrolidine ring of nicotine (fig. 2), is present in smokers at concentrations which are approximately 10fold greater than nicotine (Benowitz et al. 1983). While cotinine exhibits some pharmacological effect in vitro (Kim et a1. 1968), it produces no detectable cardiovascular effects in humans at concentrations observed in moderately heavy cigarette smokers (Benowitz et a1. 1983). In addition, its effect on smoking desire is minimal. Other metabolites of nicotine, which include nicotine-N-oxide,

Pharmacokinetics of Nicotine

34

020

Nicotine-N-oxide

~ CH3-~ ~~ '"

t-!

CH3 - 1

CH 3 lsornethylnicotinium ion

""

N

Nicotine •

N

Nornicotine

~

N "0

IN

C'H3

Cotinine Fig. 2. Primary metabolites of nicotine.

isomethylnicotinium ion, and nornicotine, have not been extensively studied for their contribution, if any, to the effects of nicotine. 1.3.2 Renal Excretion Nicotine is excreted unchanged in urine in a pHdependent fashion. At a urinary pH less than 5, an average 23% of the nicotine dose is recovered in urine unchanged (Rosenberg et al. 1980). When urinary pH is maintained above 7.0, unchanged nicotine recovery falls to 2%. It has been shown that urinary acidification increases cigarette consumption in man and nicotine self-administration in rats (Benowitz & Jacob 1985; Lang 1980).

1.4 Disposition Kinetics The disposition of nicotine has been studied primarily in otherwise healthy smokers, with one study examining the disposition in non-smokers. 1.4.1 Intravenous Administration Table I summarises the reported pharmacokinetic parameters of nicotine after intravenous administration. The variability in pharmacokinetic parameter estimates reported in table I may reflect not only intersubject variability in the disposition of nicotine, but may also be partly due to methodological differences between investigators. For example, Rosenberg et al. (1980) administered a series of intravenous nicotine bolus doses at 1 min-

ute intervals for 10 minutes. As these authors themselves have indicated (Benowitz et al. 1982), this rapid increase and decline in nicotine concentrations may have resulted in errors in computing the area, under the plasma concentration-time curve (AUC) and terminal half-life. Other investigators have administered nicotine as a constant infusion over a discrete time interval. Furthermore, each laboratory has used a different method for determination of nicotine concentrations. Differences in the specificity and sensitivity between these methods could contribute to the variability in parameter estimates. Nicotine exhibits biexponential decline in plasma following intravenous administration (Kyerematen et al. 1982). The non-renal blood clearance of nicotine averages about 1200 mlfmin (72 L/h) [Benowitz & Jacob 1985]. This value approaches normal hepatic blood flow, indicating that nicotine elimination is blood flow-dependent (Wilkinson & Shand 1975). The renal clearance of nicotine is highly dependent upon urinary pH. Rosenberg et al. (1980) found that, under conditions of urinary alkalinisation, nicotine renal clearance averaged 17 mlfmin (1.0 L/h). Upon urinary acidification, however, renal clearance increased to 245 mlfmin (14.7 LI h). Correspondingly, total clearance increased from 778 mlfmin (46.7 L/h) to 1027 mlfmin (61.6 L/h). These data indicate that nicotine undergoes glomerular filtration, tubular secretion and tubular reabsorption. The mean urinary recovery of nicotine appears to be higher, and the recovery of cotinine lower, in non-smokers compared with smokers (Beckett & Triggs 1967; Beckett et al. 1971). In addition, the data in table I indicate that the total clearance of nicotine is higher in smokers than non-smokers. While studies in the rat indicated that nicotine clearance was dose dependent (Miller et al. 1977), Benowitz et al. (1982) did not find evidence of dose dependence in humans over the range of 30 to 60 ~g/kg. As shown in table I, however, Kyerematen et al. (1982) found nicotine clearance to be substantially higher in their population than that reported by others. Interestingly, these investigators

Pharmacokinetics of Nicotine

35

also administered the lowest dose of nicotine 2.7 ~g/kg versus 25 to 60 ~g/kg). Thus, an appropriate dose-ranging study remains to be performed to definitively determine whether nicotine disposition demonstrates dose-dependence in humans. 1.4.2 Pulmonary Administration After inhalation of a cigarette, the plasma nicotine concentration rises rapidly, with peak concentration occurring within 10 minutes of initiation of smoking (fig. 3). This rapid rise in nicotine concentration indicates that the pulmonary absorption of nicotine is extremely rapid. The plasma nicotine concentration achieved following smoking is highly dependent upon individual smoking technique. These factors have been previously reviewed in detail (Darby et al. 1984). Although never directly tested, it is frequently stated that peak nicotine concentration in the brain should occur sooner after pulmonary administration than after intravenous administration (Benowitz 1986; Darby et al. 1984). This assumption is based upon the fact that the transit time from the lungs to the aorta, and subsequently the brain, is shorter than the transit time from an intravenous injection site. 1.4.3 Buccal Administration The chewing of nicotine gum releases nicotine into the surrounding medium allowing absorption of nicotine from the buccal mucosa. Plasma nicotine concentration rises considerably more slowly than after smoking (fig. 3), with peak concentrations occurring about 30 minutes after initiation of chewing. Because of this slower rise, peak to trough nicotine concentrations vary less in a subject chewing 1 piece of gum per hour compared with smoking 1 cigarette per hour (Feyerabend & Russell 1978; McNabb et al. 1982).

2. Effect of Disease on the Disposition of Nicotine To date, there is a total lack of information regarding the effect of disease on the pharmacokinetics of nicotine. This is understandable in view of

40

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30

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:E §

ec

20

~

8ro E gj

10

c. Q)

I::

~

Z

0

o

!

I

10

20

! !

30

40

I

50

60

Time (minutes) Fig. 3. Blood nicotine concentrations after smoking a cigarette containing 1.2mg of nicotine and after chewing one piece of nicotine gum (4mg). _ represents duration of exposure (adapted from Russell et al. 1980).

the fact that nicotine consumption was previously limited to tobacco consumers who were also ingesting hundreds of other chemical compounds in their tobacco use. Now that nicotine is administered as a single entity, however, examination of the effect of disease on its disposition is needed. While specific data regarding the effect of disease are not available, application of general pharmacokinetic principles allows some very reasonable assumptions to be made as to potential effects of disease. Since the elimination of nicotine appears to be dependent on hepatic blood flow, any intervention which increases or decreases hepatic blood flow may cause substantial alterations in nicotine clearance. Hepatic blood flow is altered in acute viral hepatitis (Williams et al. 1976), cirrhosis (Wood et al. 1978), congestive heart failure (Leier et al. 1984), hypotension (Feely et al. 1982) and thyrotoxicosis (Wells et al. 1983). In addition, hepatic blood flow may be significantly reduced in the elderly (Vestal et al. 1979), during exercise (Daneshmend et al. 1981) and standing compared with the supine posture (Daneshmend et al. 1981). The renal elimin-

Pharmacokinetics of Nicotine

ation of nicotine may be altered by interventions which affect urinary pH or renal excretory function. The significance of such changes on the total systemic clearance of nicotine is dependent upon the basal urinary pH in a given individual.

3. Drug Interactions Since nicotine has only recently been introduced as a single entity, little is known about its effects on other drugs or vice versa. Agents which have been shown to alter hepatic blood flow, such as epoprostenol (prostacyclin, PGIz) [Hassan & Pickles 1982], nifedipine (Feely 1984), nisoldipine (Meredith et al. 1985), glyceryl trinitrate (nitroglycerin) [Svensson et al. 1985] and several j3-adrenergic blocking agents (Parker et al. 1983), might be expected to result in alterations in the systemic clearance of nicotine. In addition, the ingestion of a high-protein meal results in substantial increases in hepatic blood flow (Svensson et al. 1983), suggesting the potential for drug-food interactions with nicotine. The clinical significance of any such interactions is unknown at present. Studies in animals suggest that long term nicotine administration may induce cytochrome P450-dependent drug metabolism (Kaur & Ali 1982; Ruddon & Cohen 1970; Wenzel & Broadie 1966). Whether this occurs in humans has not been studied. Hisaoka and Levy (1985) have demonstrated a pharmacodynamic interaction between nicotine and the hypnotic effect of ethanol and phenobarbitone in rats. For both agents, acute nicotine administration decreases the serum and cerebrospinal fluid (CSF) concentrations of the hypnotic required to produce a loss of righting reflex. Again, the clinical significance of this observation is unknown.

4. Pharmacokinetic Considerations in the Use of Nicotine Gum as an Adjuvant to Smoking Cessation The use of nicotine as a single entity is currently limited to its use as an adjuvant in smoking cessation. There are some important pharmacokinetic

36

considerations which need to be taken into account in such use. 4.1 Dosage Form and Route of Administration Nicotine gum (Leo and Co., Helsingborg, Sweden) is a cation-exchange resin containing 2 or 4mg of nicotine (Femo et al. 1973). The release rate of nicotine from the gum is dependent upon the vigour and duration of chewing. It has been reported that 'normal' chewing results in over 90% of nicotine being released within 20 minutes (Femo et al. 1973). No studies have been published examining the variability of this release. As stated previously, the absorption of nicotine from the buccal cavity is pH dependent. For this reason, a buffer has been incorporated into the gum in an attempt to maintain the buccal environment at a constant pH. While it has been stated that this buffer maintains the pH in the mouth at about 8.5 (Russell et al. 1980), there are no experimental data in the literature to support this conclusion. Such pH control is of considerable importance since it would substantially reduce variability in the absorption of nicotine. Other factors potentially affecting nicotine absorption from the buccal cavity, such as gum disease, also need to be considered but have not yet been studied. In the absence of chewing, the dosage form would be expected to release very little nicotine. Indeed, studies in dogs indicate that oral ingestion of the gum results in only about 15% loss of nicotine content as the gum passes through the gastrointestinal tract (Femo et al. 1973). These data indicate that accidental ingestion of the gum is unlikely to pose a significant risk for toxicity. 4.2 Nicotine Plasma Concentrations Upon Changing from Smoking to Nicotine Gum It has been suggested that tobacco addiction may be partly due to the effects experienced by the rapid rise in plasma nicotine concentrations in smokers after inhalation (Russell & Feyerabend 1978). This is supported by the observation that smokers ap-

Pharmacokinetics of Nicotine

37

Table I. Plasma nicotine pharmacokinetic parameters (mean ± SO) after intravenous administration"

CLT(L/min)

CLR(L/min)

CLNR (L/min)

Vd (L/kg)

tv. (min)

n

References

1.29±0.29

0.20±0.06

1.09±0.28

2.6±0.8

119±44

14

Benowitz et al. (1982)

1.31 ±0.17

NA

NA

1.0±0.1

39±4

6

Rosenberg et al. (1980)

0.92±0.15

NA

NA

2.5±0.4

133±20

5

Feyerabend et al. (1985)

2.43±0.83

NA

NA

2.0±0.3

49±5

6

Kyerematen et al. (1982)

2.07±0.41b

NA

NA

3.0±0.3

81 ±15

6

Kyerematen et al. (1982)

a b

All studies were conducted with subject's urine acidified by administration of ammonium chloride 2g 4 times daily. Data from non-smokers.

Abbreviations: CLT = total body clearance; CLR = renal clearance; CLNR tv. = terminal elimination half-life;

NA

= non-renal clearance; Vd = apparent volume of distribution;

= not available.

pear to titrate themselves to some minimally acceptable level of nicotine concentration (Benowitz 1986; Benowitz & Jacob 1985; Benowitz et at. 1983). If this assessment is accurate, then the most desirable adjuvant to smoking cessation would imitate this effect. As shown in figure 3, nicotine absorption from gum is slower than from a cigarette. Peak nicotine concentration generally occurs 30 minutes after chewing begins, compared with 5 to 10 minutes following a cigarette (McNabb et al. 1982; Russell et al. 1980). The average increase in plasma nicotine concentration after chewing 1 piece of gum (4mg) is 12 f.Lg/L, while that following a cigarette (1.3mg) average 28 f.Lg/L (Feyerabend & Russell 1978). This suggests a possible pharmacokinetic basis for the relatively low success rate of nicotine gum in promoting smoking cessation. If a high nicotine bolus is necessary to achieve the smoker's desired effect, then the slow rise and lower peak plasma nicotine concentration which occurs with nicotine gum may fail to maintain the effect needed by the smoker while seeking to overcome the psychological dependence on smoking. A route which evidenced even slower absorption (such as transdermal administration) would therefore not be an attractive alternative. Intranasal administration of

nicotine more closely approximates the time course of plasma nicotine concentrations following cigarette smoking, suggesting this route of administration as a promising alternative. In my opinion, formulation of a nicotine inhaler may provide a blood concentration profile which more closely mimics that achieved by smoking, and thereby possibly increase the effectiveness of nicotine administration in smoking cessation attempts. Several studies have shown that chewing nicotine gum hourly produces mean and trough nicotine concentrations similar to smoking cigarettes hourly (Feyerabend & Russel 1978; McNabb et al. 1982). During long term administration, however, nicotine concentrations are generally lower while subjects are on gum compared with their pretreatment nicotine concentrations from smoking (McNabb 1984). 4.3 Enzyme-Inductive Effect of Tobacco Smoking Changes in drug-metabolising capacity when a smoker is switched from tobacco to nicotine gum have not been examined in studies of nicotine gum. Tobacco smoking is well known to enhance the metabolism of several important therapeutic com-

Pharmacokinetics of Nicotine

pounds, such as imipramine, pentazocine and theophylline (Dawson & Vestal 1982; lusko 1978). Nicotine metabolism itself appears to be accelerated in smokers compared to non-smokers (see table I) [Beckett & Triggs 1967; Beckett et al. 1971]. Does drug-metabolising capacity remain elevated when a subject switches from smoking to nicotine gum? If not, what is the time course of decline in drug metabolising capacity? These questions are particularly important since those subjects suffering from the adverse effects of smoking (i.e. cardiovascular and respiratory disease) are not only the ones most likely to be encouraged to quit smoking (and thus potentially use nicotine gum as an adjuvant), but are also likely to be receiving other pharmacological agents. Until studies addressing these issues are performed, it would appear to be advisable for clinicians to carefully monitor subjects who are receiving drugs with a low therapeutic index that are eliminated substantially by hepatic metabolism and changing from smoking to nicotine gum. However, any changes in metabolic capacity are unlikely to occur rapidly. Hunt et al. (1976) found that subjects who had stopped smoking for 3 months had had relatively little change in their theophylline clearance compared with clearance values when they were smoking.

5. Perspective and Future Research From the preceding discussion it is obvious that much work remains to be done to adequately define the clinical pharmacokinetics of nicotine. In view of the recent introduction of nicotine as a single 'therapeutic' entity, the following areas deserve special attention: 1. The effect of disease on the pharmacokinetics/ pharmacodynamics of nicotine. 2. The effect of changing a subject from smoking to nicotine gum on drug-metabolising capacity. 3. The potential use of alternative routes of nicotine administration which may more closely mimic plasma nicotine concentrations observed during smoking.

38

In conclusion, nicotine administration has been shown to aid some smokers in attaining abstinence. The possibility that some subjects who fail to benefit from nicotine gum may represent 'pharmacokinetic' failures deserves further consideration. Determination of factors which influence the efficacy of nicotine as an adjuvant in smoking cessation may prove beneficial in reducing the number of tobacco consumers worldwide.

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Pharmacokinetics of Nicotine

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Author's address: Dr Craig K. Svensson, Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, MI 48202 (USA).