EXCRETION RATE ON PLASMA NICOTINE DURING

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Br. J. lin. Pharma. (1978), 5, 293-297 EFFECT OF URINARYpH

1 Br. J. lin. Pharma. (1978), 5, EFFECT OF URINARYpH AND NICOTINE EXCRETION RATE ON PLASMA NICOTINE DURING CIGARETTE SMOKING AND CHEWING NICOTINE GUM C. FEYERABEND & 1M.A.H. RUSSELL Poisons Unit, New Cross Hospital, London SE 1 4 and 'Addition Researh Unit, Institute of Psyhiatry, Maudsley Hospital, London SE5 I Plasma niotine levels produed by hewing niotine gum were ompared with those obtained by igarette smoking under onditions of ontrolled urinary ph. 2 Although absorption was slower, plasma levels omparable to igarette smoking were built up on 4 mg (but not 2 mg) niotine gum. 3 Urinary exretion of niotine was influened markedly by ph and the rate of urine flow. 4 Plasma niotine was higher under alkaline ompared to aidi onditions (P< ) but the rate of urinary niotine exretion appeared to have little effet on the plasma level. Introdution Sine the urge to smoke may be related to a need for niotine, alternative methods of administering the drug, either in aerosols or hewing-gum, have been proposed (Ferno, Lihtnekert & Lundgren, 1973; Herxheimer, Griffiths, Hamilton & Wakefield, 1967). During an investigation of the plasma onentrations produed by niotine hewing-gum (Russell, Feyerabend & Cole, 1976) urinary ph was ontrolled in order to standardise the rate of urinary niotine exretion, sine this has been shown to be ph dependent (Bekett, Rowland & Triggs, 1965; Bekett & Triggs, 1966; Haag & Larson, 1942). We also measured the urinary exretion of niotine and found that besides being ph dependent it was, under aidi onditions, proportional to urine flow. This is ontrary to previous reports (Bekett, Gorrod & Jenner, 1971a; Bekett, Gorrod & Jenner, 1971b; Bekett, Gorrod & Jenner, 1972). Methods Chewing-gum ontaining either 2 or 4 mg of niotine, buffered at an alkaline ph, was supplied by A.B. Leo, Helsingborg, Sweden (Ferno et al., 1973). The test igarette was a brand with a niotine yield of 1.3 mg. A single volunteer was used. He was a healthy male smoker, aged 38 years, who regularly smoked just over 20 igarettes per day and inhaled deeply. Before eah day's experiment he refrained from smoking for at least 12 h. The urine was aidified by administering 2 g doses of ammonium hloride in gelatine apsules at h on the day before and 07.00, and h on the day of an experiment. The same dosage of sodium biarbonate in gelatine apsules was used to maintain the urine alkaline. Fluid intake was not ontrolled. During eah experiment the subjet was ambulant, took fluids as usual, and had lunh between 13h30minand 13hSOmin. Plasma and urine niotine levels were studied on six separate days when the subjet was either smoking or taking 2 mg or 4 mg niotine hewing-gum, eah under both aidi and alkaline ontrol of urinary ph. On smoking days, one igarette was smoked to about 3 mm from the tip over 5 min one an hour for 8 h. When taking niotine hewing-gum, one piee was hewed for 30 min every hour for 8 h. The dose of niotine administered over 8 h was 10.4, 16.0 and 34.0 mg respetively for the igarettes, 2 mg and 4 mg gum. About 91% of the niotine in the gum is released during 30 min hewing (Ferno et al., 1973) and more than 90% of niotine in mainstream smoke is retained after inhalation (Armitage, Dollery, George, Houseman, Lewis & Turner, 1975). The bladder was emptied at h. Urine samples were then olleted every hour just before a igarette or gum was taken, starting at h. The volume and ph of the urine were measured immediately and aliquots stored at -200C. Blood samples (5 ml) were obtained from a forearm vein via an indwelling annula. The plasma was separated within 3 h and stored at -200C. Blood was taken hourly just before starting eah igarette or gum on six different experimental days. This frequeny of

2 294 C. FEYERABEND & M.A.H. RUSSELL u en Cigarettes Chewing gum Figure 1 Plasma niotine levels under onditions of ontrolled aidi urinary ph when (O) smoking one igarette and (U) hewing one 4 mg niotine gum every hour for 7 h. sampling did not allow omparison of peak plasma levels. On two further days, to ompare the rates of absorption of niotine from igarettes and the 4 mg gum, more frequent samples were taken at 7, 15, 30 and 60 min after starting eah hourly gum or igarette (Figure 1). Niotine in plasma and urine was analysed by gasliquid hromatography (Feyerabend, Levitt & Russell, 1975). Results Niotine absorption was muh slower from the hewing-gum than from igarette smoking, min being required to reah peak values ompared with less than 2 min after a igarette (Figure 1). The average ±s.d. inrease in plasma niotine after eah piee of gum (4 mg niotine) was only 11.9 ± 2.4 ng ml-' ompared with 27.8 ± 4.6 ng ml-' after eah igarette (1.3 mg niotine). Plasma niotine onentrations similar to those from smoking were built up on the 4 mg gum, but on 2 mg gum they were lower. Taking the areas under the urves in Figure 2, with those produed by smoking as representing 100%, the plasma niotine onentration from the hewing-gum was 60% and 114% for the 2 mg and 4 mg gum respetively under aidi onditions; 77% and 118% when the urine was alkaline. When the peak levels are inluded (Figure 1) the area under the urve for the 4 mg gum is 91% of that produed by igarettes. The subjet reported no desire to smoke while on the 4 mg gum but was not satisfied by the 2 mg gum. Plasma niotine onentrations were slightly higher under onditions of alkaline ompared with aidi urine (Figure 2). From the areas under the urves in Figure 2, the inreases in plasma niotine whih -j 7 E 0)._ 0 o E o Cu a [ b [ C 30 [ 20F 10L ~~~~~~~~I t II t Figure 2 Plasma niotine levels immediately before (a) smoking one igarette, (b) hewing a 4 mg and () 2 mg niotine gum every hour for 8 h. 0 aidi ontrolled urinary ph ( ); * alkaline ontrolled urinary ph ( ). The differenes between aidi and alkaline onditions when smoking igarettes and taking 2 mg niotine gum are highly signifiant (t = 6.1 and 7.1 respetively, d.f. 8, P < 0.00) but only just signifiant on a one-tailed test when taking 4 mg niotine gum (t = 2. 1, d.f. 8, P < 0.05). ourred with the alkaline versus aidi urine ondition were 66%, 35% and 30% respetively for the 2 mg gum, 4 mg gum and igarettes. The effet of urine ph on niotine exretion is shown in Figure 3. Under aidi ontrol 18 to 30 times more niotine appeared in the urine than under alkaline onditions. Total niotine exretion over 8 h was 1,024, 1,072 and 1,308 jig for the 2 mg, 4 mg gums and igarette smoking respetively under aidi onditions; ompared to 33.7, 59.2 and 43.6 gg under alkaline onditions. The urinary niotine exretion, under onditions of ontrolled aidity, was related to urine flow and was higher at midday (between 11 and 13 h) when urine flow was maximal (Figure 4).

3 ph EFFECTS ON PLASMA AND URINARY NICOTINE 295 C) 0 a) Z._ OL Figure 3 Urinary exretion of niotine when smoking a igarette (0, 0) hewing a 2 mg (A, A) and 4 mg (0, *) niotine gum every hour for 8 h. Open symbols aidi ontrolled urinary ph ( ); Closed symbols alkaline ontrolled urinary ph ( ). Disussion The data suggest that aumulation of niotine ours in plasma when taking niotine ontaining hewinggum. Although absorption was slower, plasma levels --T omparable to igarette smoking were built up on 4 mg (but not 2 mg) niotine gum. With hourly niotine dosage, plasma onentrations produed by 4 mg niotine by gum were 91% of those produed by 1.3 mg niotine via deeply inhaled igarette smoke. It is not known how muh the pharmaologial rewards of inhaled igarette smoking are due to some effet of the rapid plasma niotine peaks or to the maintenane of a ertain trough level. This probably depends on the type of smoker. The data from this study suggest that niotine hewing-gum is more suited to trough maintenane or to providing whatever pharmaologial effets are produed by the slower bual absorption of niotine as in the ase of noninhaled igar smoking. The rate of niotine absorption from the gum is limited partly by the rate of bual absorption but also by the rate of it release from the gum:- 18%, 36%, 61% and 91% respetively after 2, 5, 10 and 20 min hewing (Ferno et al., 1973). The urinary exretion of niotine was influened markedly by ph and the rate of urine flow. The influene of urinary ph is in keeping with previous studies (Bekett et al. 1965; Bekett & Triggs, 1966; Haag & Larson, 1942). However, the very lear relation of the rate of urinary niotine exretion to urinary flow, under aidi onditions, is not generally aepted and is in fat ontrary to the onlusions of Bekett and his olleagues (1971a, 1971b, 1972). In his earlier work Bekett also found that the amount of niotine exreted in urine was influened by the rate of urine flow (Bekett & Triggs, 1966). However, in subsequent publiations (Bekett et al., 197 la, 197 lb, I i> ~a C 4.5.E b r **- ~ ## 3: 170 I C- 130 \ C, E 90 g / 50 >% 370- o C 0) o Es C x ) L , [ \ 90 M L- _e 50_- ; 2 4t 6 8 Figure 4 Relation of urinary niotine exretion to urine flow rate under onditions of ontrolled aidi urinary ph when (a) hewing 2 mg niotine gum, (b) smoking one igarette and () hewing 4 mg niotine gum every hour for 8 h.

4 296 C. FEYERABEND & M.A.H. RUSSELL 1972) he and his olleagues ame to different onlusions reporting, for example, that 'when the urine is adjusted to an aid ph the exretion of otinine but not of niotine is affeted by hanges in urine output' (Bekett et al., 197 lb). In another report, they mentioned 'the volume dependent exretion of otinine but not niotine' (Bekett et al., 1972). A possible reason for this apparent disrepany may be that the experiments in whih they failed to find a urine-flow effet involved a single relatively small dose of niotine given to subjets who had not smoked for as long as 36 h. Under these onditions, apart from the first hour, the niotine exretion rate was usually below 1.0,ug/min. It is possible that at suh low levels their measurement of niotine may have been insuffiiently sensitive to detet the influene of urine flow rate superimposed on the deline urve following a single small dose of niotine in niotine-depleted subjets. Despite the fairly large (18-30 fold) variation in urinary niotine exretion produed by hanges in ph and urine flow, the effet on plasma niotine onentrations was relatively small. Indeed the plasma levels did not seem to be notieably affeted (Figure 2) when the urine flow and niotine exretion rate were maximal at 2 to 4 h after the start of eah experiment (Figures 3 & 4). On the other hand, plasma onentrations were 30%-66% higher under onditions of alkaline ompared with aidi urine. The fat that plasma niotine levels were affeted by the ph but not by the rate of urine flow suggests that the effet of ph on the plasma levels may have been mediated less by the influene on urinary niotine exretion rate than by some other mehanism suh as an influene on niotine absorption or one of the niotine reyling proesses (Russell, 1976). The effet of ph on plasma niotine onentrations helps to explain the findings of Shahter, Kozlowski & Silverstein (1977) who showed that igarette smokers ould be made to modify their igarette onsumption by manipulating their urinary ph. Compared with the doses of niotine administered over the 8 h experimental periods (10.4, 16.0 and 32 mg respetively for igarettes, 2 mg and 4 mg gum) the amounts exreted in the urine were trivial even under aidi onditions (1.3, 1.0 and 1.1 mg, or 12.5%, 6.3% and 3.4% respetively for igarettes, 2 mg and 4 mg gum). This may explain why major hanges in urinuary exretion of niotine had a relatively small effet on the plasma levels. Despite the marked redution in urinary exretion under the alkaline onditions, exessive aumulation of niotine did not our. These findings suggest that in this subjet the plasma niotine was influened more by the rate of metabolism than by the rate of exretion of unhanged niotine in the urine. The tendeny for plasma niotine to fall just after lunh (Figure 2) annot be explained by an inrease in niotine exretion, for this was maximal 1-2 h before lunh (Figure 4). It ould, however, be explained by an inrease in the rate of metabolism of niotine brought on by the postprandial inrease in blood flow to the gut and hene the liver (Henry & Meehan, 1971). On the basis of the afternoon plasma niotine onentration when taking the 2 mg niotine hewinggum, the subjet in this study was not markedly atypial ompared to a sample of 15 smokers attending a withdrawal lini; they averaged 10.9 ng/ml and ranged from 5.4 to 21.8 ng/ml under onditions of flutuating urinary ph (Russell et al., 1976). Impliations from data based on a single subjet obviously require repliation with more subjets. Nevertheless, these findings do suggest that (1) 4 mg niotine hewing-gum has some potential as a pharmaologial substitute for smoking; (2) Notwithstanding Bekett and his olleagues previous work (1971a, 197 1b, 1972), urinary flow influenes the niotine exretion rate under aidi onditions; (3) Flutuations in urinary niotine exretion have a relatively small effet on plasma niotine onentration; (4) The higher plasma niotine onentration when taking sodium biarbonate as opposed to ammonium hloride may be mediated more by an influene on niotine absorption or one of the niotine reyling proesses than by hanges in urinary exretion of niotine; (5) There may be a tendeny for the plasma niotine onentration to derease more rapidly after lunh whih ould ontribute to an inreased urge to smoke at this time. We thank A.B. Leo and Co., Helsingborg, Sweden for supplying the niotine hewing-gum; Peter Rutledge, our willing subjet; the Medial Researh Counil and Department of Health and Soial Seurity for finanial support; and Jean Cruth for seretarial help. Reprint requests should be addressed to M.A.H.R. Referenes ARMITAGE, A.K., DOLLERY, C.T., GEORGE, C.F., HOUSEMAN, T.H., LEWIS, PJ. & TURNER, D.M. (1975). Absorption and metabolism of niotine from igarettes. Br. med. J., 4, BECKETT, A.H., GORROD, J.W. & JENNER, P. (1971a). The analysis of niotine-l'-n-oxide in urine in the presene of niotine and otinine and its appliation to the study of in vivo niotine metabolism in man. J. Pharm. Pharma., 23, Suppl. 55S-6 IS. BECKElT, A.H., GORROD, J.W. & JENNER, P. (1971b). The effet of smoking on niotine metabolism in vivo in man. J. Pharm. Pharma., 23, Suppl. 62S-67S.

5 ph EFFECTS ON PLASMA AND URINARY NICOTINE 297 BECKETT, A.H., GORROD, J.W. & JENNER, P. (1972). A possible relation between pka, and lipid solubility and the amounts exreted in urine of some tobao alkaloids given to man. J. Pharm. Pharma., 24, BECKETT, A.H., ROWLAND, M. & TRIGGS, E.J. (1965). Signifiane of smoking in investigations of urinary exretion rates of amines in man. Nature, 207, BECKETT, A.H. & TRIGGS, E.J. (1966). Determination of niotine and its metabolite, otinine, in urine by gas hromatography. Nature, 211, FERNO, O., LICHTNECKERT, SJ.A. & LUNDGREN, C.E.G. (1973). A substitute for tobao smoking. Psyhopharmaologia, 31, FEYERABEND, C., LEVITT, T. & RUSSELL, M.A.H. (1975), A rapid gas-liquid hromatographi estimation of niotine in biologial fluids. J. Pharm. Pharma., 27, HAAG, H.B. & LARSON, P.S. (1942). Studies on the fate of niotine in the body. 1. The effet of ph on the urinary exretion of niotine by tobao smokers. J. Pharma. exp. Ther., 76, HENRY, J.P. & MEEHAN, J.P. (1971). In The Cirulation, p Chiago: Yearbook Medial Publishers In. HERXHEIMER, A., GRIFFITHS, R.L. HAMILTON, B. & WAKEFIELD, M. (1967). Cirulatory effets of niotine aerosol inhalations and igarette smoking in man. Lanet, ii, RUSSELL, M.A.H. (1976). Tobao smoking and niotine dependene. In Researh Advanes in Alohol and Drug Problems, ed Gibbins, R.J. 3, New York: Wiley & Sons. RUSSELL, M.A.H., FEYERABEND, C. & COLE, P.V. (1976). Plasma niotine levels after igarette smoking and hewing niotine gum. Br. med. J., 1, SCHACHTER, S., KOZLOWSKI, L.T. & SILVERSTEIN, B. (1977). Effets of urinary ph on igarette smoking. J. exp. Psyhol: General, 106, (Reeived June 14, 1977)

clinical conditions using a tape recorder system

clinical conditions using a tape recorder system Thorax (1964), 19, 125 Objetive assessment of ough suppressants under linial onditions using a tape reorder system C. R. WOOLF AND A. ROSENBERG From the Respiratory Unit, Sunnybrook Hospital (Department