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39 t9rtrate was not stipulated so the equivalent of nicotiye base cannot be calculated, but it could have been as little as 3.3 mg per capsule. The authors, who believed that this dosage would substantially in- crease blood nicotine levels, interpreted the fact that cigarette con- sumption was reduced by only 7.4% as tndicating that nicotine is not an lmportant determinant of smoking behavior (25). We are not aware of any published data on plasma nicotine levels following the Ingestion of nicotine. One of our laboratory colleagues, who usually smoked just over 20 cigarettes per day, ingested nicotine bydrogen(})-tartrate in gelatin capsules (12 mg per c2psule, equiva- lent to 4.0 mg nicotine base). Starting with a dose of S mg nicotine base taken in the morning following at least 12 hr of abstinence from smoking and with his urine controlled at an acid p13 by ammonium chloride, we found no detectable elevation of plss= nicotine. The dose was gradually increased, and it took ;a mg of nicotine bsse to produce plasma nicotine levels around •10 ng/ml (Fig. 5). In the sa^:e subject (Fig. 4), under identical conditions (12 hr abstinence front smoking; acidic control of urine pN; ad libitum f'.uids), a plasma nico- tine concentration of 40 ng/ml was reached after the second ci;aret:e (1.2 mg nicotine per cigaretie) and after the fourth piece of r.icotine ctrewing guni (4 mg nicotine base per gum). The long delay of 31 hr before the appearance of nicotine in the plasma Was probably due to the fact that much of the dose remained in the stomach. When the subject drank 270 ml water with the capsules and a further 270 ml alter 30 min, absorption was improved and smoking levels of plasma nicotine were achieved by ingestion of 28 mg nicotine base (Fig. 5). Figure 5 also shows the high nicotine concentrations In saliva com- pared to plasma, as has been mentioned already. The average saliva to plasma ratios were 7.8 (SD 4.6) after 44 mg and 7.3 (SD 1.9) after 28 mg nicotine. The ratio is clearly less just after lunch, 4.6 com- pared to 13.2 (mean of the three values preceding lunch) for the 44- mg nicotine experiment, and 3, 0 compared to 10. 2 for the 2S-mg nicotine experiment, C. Absorption through the Lungs The contrast, found by Armitage ct aI. using their animal model [203, between the rapid response to a single puff of smoke Introduced into the lungs compared to 30 such puffs when restricted to the mouth has been mentioned above. Indeed, they went further to show that smoke containing 170 Ng nicotine introduced into the lungs of a cat had a similar effect on the blood pressure as 120 pg nicotine base injected into the femoral vein [20). a

' tuncl ^n4 r.icotine Use lire Ihl =^4 nicctir.e lire 11'.1 b11e FIG. 5. Plasma and salivary nicotir.e concentrations after inges- tion of nicotine in gebtin capsules. The doses a re expressed as nico- tine base. The subject took fluids ad llbitum after the 44-mg dose, but additional fluids were forced after the 29-:r:g dose when 270 ml Water was uken with the capsules at 10 A. M. and a further 270 ml at 10.30 A.M. and 3.30 P.M. Urine controlled at acid pli. no increase in plssma nicotine after smoking and tnhaling a cig- arette Is shown in Figs. 3 and 4. 7bese profiles are similar to those of otber stt:dles (26, 27]. It is clear from these plasma nicotine peaks that pulmonary absorption Is extremely rapid and of a similar order to intravcnous dosage. However, smokers vary greatly In the degree to which they inhale. Peak plasma nicotine levels of regular cigarctte smokers vary more than 10-fold and, In our expericnce, range from about 5 to 70 ng/ml. The level dcpends very much on the individual inhalation pattern of the smoker and correlates only about 0.6 with daily cigarette consumption and even less (0.4). with the nicotine yield of the cigarette smoked. In a technically sopbisticaied study, Armitage and Dollery (27), using ctgarettes spiked with "C-nicotine, showed that smokers who Inhale absorb up to 90% of the nicotine In the smoke which they draw N av N ~

i ~~ ' • z - CIGARETTE SDIOKI\G ,.~c~• 41 into their mouths; presumably the proportion is even higher for smoke taken Into the lungs. Although the pli of the smoke of many cig- arettes is acidic (see above), absorption of nicotine via the lungs is nevertheless extremely rapid. This Is probably partly due to "'. the vast surface area for absorption and partly that the pit of the alveolar surface fluids is around 7.4 as opposed to 5.5 in the case of cigarette smoke. Vll. PLaSNt.a NICOTINE AFTER INH.aL4TIOV AND 1\TRaVE\OUS DOV.GE Although Armitage's bioassay technique with cats showed that 170 pg nicotine Introduced into the lungs was equivaler.t to 120 Vg via the femoral- vein (20), human studies suggest that intalation is no !ess efficient than intrat•enous dosage, at least so fa r as the ger.era:'e:t of high plasma levels is concerned. With inlLiled ci;are:te smoking, nicotine dosage Is intermittent, takir.g the form of a series of high- nicotine boll associated with each Inhaled pulf. Though plasma nicotine levels produced by cigarette smol:ir.g can be studied; the amount of nicotine ukken in from a ci„aret:e is diffi- cult to determine. The nicotine yield of the cib.irece Is no guide as it depends on the n•ay the ciganntte is puffed, and the nicotine ir.tal:e then depends on the extent to which the puffs are inha!ed. The plasma levels are further influenced by the rate of puffing. Nicotine yields of cigarettes are arbitr-arily determined by standardized puffing on a smoking machine-one 35 ml puff of 2 sec duration taken at a rate of one per minute to a butt leagth of 20 mm or the tip ovcrWrap plus 3 mm, whichever is the greater, is the usual sund.•trd used. But some smokers take 70 ml puffs every 20 sec and smoke to a shorter butt lengtb, so that it Is possible for a smoker to gct more than double the standard yield of nicotine from a cip rette. On the other hand, some smokers puff and Inhale very little. The problems can be further illustrated by t3kir.g an example of two cigarettes with identical nicotine yields as measured by standard meth- ods. One Is a king-size cip rettr with a sttndard yield of 1.7 mg nico- tine from 30 puffs taken over 10 min. The other Is a small-size cig- arette (still very popular In England) which yields 1.3 mg nicotine from five standard puffs taken over 5 rnin. Not only will the concen- tration of nicotine per puff be twice as high with the small cig3rette (with implicattons for brain nicotine levels, see below), but the same dose will be taken in half the time.

25 , 201 101 SJ 0 10 20 :0 40 50 Go 0 to 9o loo an Time (mins) Bolus injettiur.s 4„er 4 minuies FIG. 6. Plasma nicotine levels after intr.tvenous nicotine (1 mg nicotine base given as five rapid bolus lnjcctioes at a rate of one per atinute), Subjects P.R. (W-t 157 ]b) and H.H. (wt 174 lb) were regular smokers of 20 or more cigarettes per day who claimed and appeared to Inhale deeply. M.R. (wt 182 lb) was an occasion.kl cigar smoker who had given up cigarettes 10 years ago. Urine eontrollcd at acid pH. To gain some idea of the relation of nicotine dosage to plasma levels, we measured plasma nicotine in three subjects following an Intravenous dose of 1 mg nicotine base given as live rapid bolus injections of 200 yg nicotine at a rate of one per minute. The subjects had not smoked for at least 12 hr and the urine was acidified by prior administration of ammonium cbloride. The results are shown In Fig. 6. The tacreases In plasma nicotine produced by the Injections were as follows: subject H. H. 6.2 ng/mt, subject P. R. 7. 5 ng/ml, subject At. R. 21. 0 ag/ml. The plasma nicotine increases after the first cigarette of the day was 7.2 ng/ml for subject H. H. and l l.1 r.g/ml for subject P. R. (see Fig. 7 below). Howevcr, as mentioned above, we do not :mow the true dose

;~.. . vii;• CIGARETTE SMOKING •i•s l 43 4 «, .r of nicotine they were inhalfng from tbetr 1.3 and 1.4 mg nicotine cig- 4t., A. -.arettes. It could have been as low as 0. 5 mg or over 2.0 mg. In another experiment (see Fig. 8 below), rapid injection of 1.78 mg Aa; nicwtlne base intraveneously produced plasma nicotine peaks equiva- lent to those obtained from smoking a cigarette with a nicotine yield •`~of1.2mg. .~y ,. ~ j~.• The plasma nicotine levels In Fig. 6 are lower than those shown In ~ Figs. 3 and 4. They are also lower than the cigarette smoking levels ;~ of the Isaac and Rand study [26], mean 25 ng/ml (range 12 to 44 ng/ ~:`ntl), and the Armitage and Dollery study [27], range 31 to 41 ng/ml, t•Thts might be partly due to the fact that most of the cigarettes used in these studies had nicotino yields which were slightly over 1 mg. However, as explained above, we cannot tell how much nicotine was taken In from these cigarettes to generate the plasma levels observed. The slightly higher levels of the Armitage and Dollery study are prob- ably due to the fact that they --•er•e from arterial as opposed to venous blood samples. Armttage and Doliery [27] attempted to make a direct comparison of nicotine intake by inhalation and intravenous injection and concluded that the plasma nicotine levels produced by the two troutes boresa similar relation to the dose administered. In general, it seems that plasma nicotine concentrations can be in- creased no less rapidly and efficiently by cigarette smoking than by in- trarenous In ection. The dilution and dispersal j greater of nicotine boll ; given Intraveneously see:n to roughly counterbala:,ce the time t4ken for absorption through the lungs so that the two routes of administration appear to genctate similar venous plasma levels. But it does not fol- low that In the case of brain levels (sce below) the relation of nicotine dosago to level produced would be so sirclla r for the two routes of ad- ministration. More systematic studies arc clcarly :,ccessary to es- tablisb the nicotine dosag¢ of habitual smokers. VllI. URI\ARY EICRETIO\ OF \7COTl;,%"E As Is the case with its absorption, the urinary excretion of nicotine to pH dependent. At a pli of 5.5 or )ess, the nicotine is almost 7.ctally lonized and cannot be reabsorbed through The rcnal tubules. Under these conditions, 30 to 40% of an intravenous dose is escre..ed in the urine as unchanged nicotine E103. On the other hand, at pH 8 most of the nicotine Is reabsorbed through the tubules and even the bladder. Excretion of the metabolites Is largely indcpender.t of pH. Beckett [10) concluded That urinary excretion of nicotine was unaftecsed by ot

44 RUSSELL AND FEYERABEND urine flow, but we have found It to be proportional to the rate of urine flow under acidic conditions (26]. We have also found that plasma nicotine levels are affected slightly by manipulating the urinary pH with ammonium chloride and sodium bicarbonate (28]. L\. RECl'CLI1G OF XICOTL\'E There are at least three recycling processes which could affect plasma nicotine levcls. These will be mentioned only briefly as they have been discussed more fully elsewhere (5). 1. Sailvogaslric cycle: We probably to pH pariition mentioned above, nicotine Is excreted Into the saliva and stomach. This nico- tine would be reabsorbed in the intcstine, but since it w•ould then be largely metabolized in the liver, this cycle would have little effect on maintaining plasma nicotine levels, apart from small amounts of salivary nicotine ubich might be reabsorbed through the buccal mu- cosa. 2. Nicotine-N-o.%Ide reduction: There is an \-oxide reductase system in the colon (either in the intestinai wall or boH•el flora) which reduces nicotine-l-o.dde to nicotine. Any of the N-oxide excreted in the bile would therefore be reabsorbed as nicotine. Though this would mostly be returned to the liver and remctabolizcd, some must cscape into the general circulation as nicotine-1'-:i-oxfde ad:ninistered orally or rectally results in the appearance of nicotir.e In the urine (29). 3. Reabsorption from urinary bladder: Travell [30) has dcmon- stratcd rapid absorption of nicotine from the bladdcr under alkaline conditions. Under r,orr.ul conditions of fluctuating urinary pH, a sit- uation could occur where the bladder is half-filled with acid urine con- L-ktning a high concentration of nicotine. Subscqucnt addition of alka- line urine could raise The pli of the urine in the bladder sufficiently for the nicotine to be reabsorbed before the urine is voidcd. Such a cycle would be an in:ermittent rather than continuous evcnt. X. PROL401GED HEAVY S11OKIrG The data in Fig. 4 and the study of Isaac and Rand [26J suggest that some accumulation of nicotine occurs with repeated dosage. Fig- ure 7 shows the plasnta nicotine levels of two subjects over a 7-br period In which they smoked at a rate of three cigarettes per hour. C

45 • • • • L . . 1 . ^ k i. • i • . ~`. • : . , 7 G tiQM lur.ch !.7i1tJ ~ ^ • i • ^ i • • 10 cKUette fnctea tiqhl iuncn ~:•• ••: 1 rmc FIG. 7. Plasaa nicotine levels during forced prolonged heavy smoking at a rate of three cigarettes per hour for 7 br. Each cig- arette was smoked over precisely 5 rain, and blood samples were taken just before and 2 mLn after each cigarette. Both subtects were regular smokers whose usual smoking frequency was just over 20/ day. Nicotine yields of the cigarettes were 1.3 for P. R. and 1.4 mg for H.H. Urinary pH was uncontrolled. 6:

46 RUSSELLANM FEYER4BEND The blood samples were taken just before and 2 min after each ciga- rette which was smoked for precisely 5 min. The frequency of smoking was much higher than was usta3l for these subjects, but inhalatton was not forced. Apart from the peaks and troughs related to each ciga- rette, there Is a clear tendency for the plasma nicotine to increase over the first 3 hr after which It appears that a "steady state" is reached. This "steady state" is unlikely to be due to a high rate of urinary nicotine excretion as this was negligible (<1.0 mg in 7 hr) In the one subject ()ill) In whom it was measured. Apart from the increase In nicotine metabolism due to higher nico- tine concentrations, the maintenance of the "steady state" could de- pend in part on self-regulation by the smoker taking the form of a re- duction in inhalation. There is some suggestion that the two subjects inha)ed less nicotine once a"steady state" was reached but this was not statistically significant. The mean plasma nicotine 9ncrcase per cigarette was 9.4 ng/ml (SA 5.9) before lunch and 7.8 ng/ml (ED 6. 5) afterwards It = 0.0, df 19, SS) for subject P. R. ; 10.0 ng/rnil (SD 2.:) before and 6.7 ng/ml (SD a.;) after lunch it = 2.0, df 19, NS) for sub- ject H.H. The after-lunch means are similar to the increases shown by the same subjects after 1.0 mg nicotine IV (Fig. 6) w•hich were 7.5 and 6.2 ng/ml, respectively, for P.R. and 11. H. This suggests that after lunch they were both taking in about 1.0 mg nicotine from each cigarette, but that before lunch they were inha)ir.g a little more. \I. PLASNLk li4LF-LIFE OF h7COT1 NE There are no adequate p):armacokinetic studies of the elimination rate of nicotine from plasma. Isaac and Rand [26) simply stnted that "the plasma baif-life was less than 30 minutes In all four subjects." 71ey then went on to mention on initial rapid phase due probably to distribution and a slower phase possibly due to metabolism and ex- cretion. Armitage and Dollery (27) "assumed a one-compartmcnt model" but clearly meant a two-compartment model since they used points between 10 and 50 min after the completion of the cigsrcitc for their calculation. On this basis they found half-lh•es ranging from 24 to 84 min with a mean of 40 mLn. Both these studies based their cal- cul3tions an data from nicotine-dcplcted smokers who had smoked a sing)e cigarette and who had no control of urinary pH. In a recent study comparing plasma nicotine levels produced by cigarette smoking and nicotine chew•ing-g:.m i311, we had plasma nicotine data for 21 subjects who had been smol:Lng normally for

CIGARETTE SMOKING • {;~+~' - j; '• 10 / 60 i • g ~ ~ ,~ / / / ~ `d I •.~ 30 I 47 ,- 10X! S00 600 :03 FIG. 8. Plasma concentrations and urinary excretion of n?cotir.e following Intravenous nicotine injectior.s and cigarette smokino. The dose of nicotinv for all three injections was 1. 79 mg of the basc (0. 025 mg/kg) Injected rapidly over 1 min. The six cigarettrs were smoked at a rate of 2/br and blood samples were taren just before and 2 min after each cigarette (1.2 mg nicotine). Lrine controlled at acid pFi. several hours. The avcragc peak'.evel of 31.5 ng/ml at 2 min de- clined to only 25.2 ng/mI at 25 min after the last cip rette. Although only two points were avaiisble, this did suggest to us that after sev- eral hours of smoking the hatl-lifc of nicotir.e In plasma might prove to be more than 1 hr or at least somewhat longer than stated in the two studies cited above. In collaboration with G. Volans, we have just started a study to investigate The plasma half-life of nicotine with and without tissue saturation and under conditions of high and low con- centrations of nicotine. This study Is still In proyress but the data from the first subject are shown In Figs. 8, 9, and 10. After 12 br abstinence from smoking, the subject was given 1.78 mg (0.025 mg/kg) nicotine base by rapid I.v. injection over I min. Blood samples were taken over the next 60 minutes after which the subject smoked two cigarettes an hour for 3 bours, blood being sam- pled 2 minutes and 25 minutes after each cigarette was completed. The i.v.•nicotlnc tnjectton was then repea:.cd and followod by blood i. v. nicotine over Imin • ri4trftlt t^Cfe9 over S mi1 ~ 2 reus etttn in 10 min ,_ . Dltsma ourine \ / \ \` ~, \\ \ \ t;rine

48 100.1 50 RUSSELLAI.'D F£YERAI3END Ist injection I 2nd injKtion %J C C C C 3rd injeclion 0 1 t 1 luncn A S 6 T d Timt, hourS FIG. 9. Pa1se rate changes af:cr nicotine tnjections and after smoking cigarettcs (C) duri:g the cxperimcnt sLown in Fig. S. I sampling for a further 3 hr when a 3rd i.v. nicotine injection was given followed by blood sampling over the final 2 hr. Urine samples were collected hourly and the urine controlled at an acid pli by taking am- monlum chloride. The plasma levels and ur3nary excretion of nico- tine are shown in Fig. S. the pulse rate in Fig. 9, and the plasma nicotine profiles of the three I.v. Injections In Fig. 10. The Increase in pulse rate with each injection obviously requires a saline control. Howerer, it Is clear that despite the plasma nicotine peaks produced by each cigaretie, they soon lose their capacity to quicken the pulse. The preliminary analysis of the data shows biexponenttal decay which fits a two-compartment open model. The alpha half-life for the lsl to 3rd Injections Is 3.3, 2.1, and 3.4 rain, respectively, and the bMa half-li.fe 66, 81, and 93 min, respectively. The correlation between the actual data and the predictions from the model Is 0. 99 in all three instances. The results show that there Is no saturation of the overall biotransforai,tion processes at these concentrsttons, but the time-related increase in plasma half-life suggests the influence of a third slow perfusion compartment (e.g., fat). The fact that this is not picked up as a triexponential decay after each dose is probably due partly to the very low concentrations and partly to the relatively short time period studied (mar.imu.-n of 3 hr after the second tnjection).