Pharmacokinetic Evaluation of Published Studies on Controlled Smoking of Marijuana

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1 Pharmacokinetic Evaluation of Published Studies on Controlled Smoking of Marijuana G. Sticht and H. Käferstein Institute of Legal Medicine, University of Cologne, Melatengürtel 60-62, D Köln, Germany ABSTRACT The recommendation for laying down a limiting value of tetrahydrocannabinol concentration in plasma raises the question of dose-effect-relations. For this an essential precondition is the determination of pharmacokinetic parameters as resorption, distribution and elimination constants as well as distribution volume and bioavailability. We have evaluated results of 5 studies which contain data relating to THC-levels in plasma after smoking of marijuana cigarettes with defined content of THC. The pharmacokinetic parameters developed out of these studies under presumption of a two compartment model leads to a time plot of average THC-concentrations as well as minimum and maximum curves at which the standard deviation of the pharmacokinetic parameters are taken into account. In particular during resorption and in the late elimination stage estimation of plasma levels of THC is accompanied by a wide dispersion. Nevertheless estimation of THCconcentrations out of the amount of consumed marijuana at a stated time or on the other hand interval out of THC-concentration in plasma is to be derived using the developed curves of THC-concentrations. INTRODUCTION The knowledge about influences of psychotropically active substances like narcotics and drugs on ability to drive is much less than about effects of alcohol. While alcohol is distributed nearly exclusively in the body water, the pharmacokinetics of most other substances is more complex because of their lipophility. One prediction for a better understanding of dose-effect-relations of drugs and other active agents is evaluation of pharmacokinetic models and determinations of corresponding datas. An open twocompartment model describes the course of plasma concentration of many psychotropically active agents. We have presented statistically evaluated pharmacokinetic parameters of 30 relevant drugs which allow to estimate the range of concentration in the various phases of plasma concentration-time curve (Käferstein et al. 1990, Graß 1989). Attempts in Germany for laying down a legal limiting value of tetrahydrocannabinol (THC) concentration in plasma raises the question of dose-effect-relations. For this an essential precondition is the determination of pharmacokinetic parameters as resorption, distribution and elimination constants as well as distribution volume (V d ) and bioavailability (B). Some pharmacokinetic data of THC after smoking of marijuana cigarettes are given by Chiang and Barnett (1984) but these values are not sufficient to plot a concentration-time curve. Some investigators have reported an elimination half-life of THC of 20 hours and more (Hunt and Jones 1980, Peat 1989). These results might be caused by the applied 397

2 methods for quantitation of THC. We have considered only studies with GC-MS estimation of THC because of the secure identification and quantitation by this way. RESULTS Studies on controlled smoking of marijuana permit estimation of most pharmacokinetic parameters as resorption, distribution, and elimination constant but not the distribution volume. This parameter is only deductible from intravenous administration because a high loss of THC should result from smoking and oral intake. Intravenous application Studies with intravenous administration of THC are performed by Hollister et al. (1981) and Lindgren et al. (1981). Unfortunately the authors documented not the individual body weights and the individual time concentration curves. In Table 1 the pharmacokinetic parameters calculated by our self provided computer program (Sticht et al. 1986) are presented. Table 1 Pharmacokinetic Parameters after IV-Application of THC (2 studies with 29 probands). Dose 5 mg THC, body weight unknown Probands β (h -1 ) α (h -1 ) V d (L) V c (L) (Hollister et al. 1981) (Lindgren et al. 1981) heavy users (Lindgren et al. 1981) light users Mean SD There is a very good agreement between the studies concerning the constant of distribution. But there are some differences between the light and the heavy users. Nevertheless it can not be said, that heavy users would eliminate THC faster than the other group. The mean volume of distribution is 236 L, but the two groups are clearly distinguishable. But this is difficult to interpret because the body weights are not known. Oral application We could find only one published study after oral intake of 20 mg THC (Hollister et al. 1981). The pharmacokinetic parameters are given in Table 2. The data were derived from average value curve. The bioavailability (B) is calculated with the mean volume of distribution from Table 1 and only 6% The constant of distribution seems to be much lower 398

3 than after intravenous injection. It could be possible that there is an overlapping of slow resorption, distribution and elimination. Table 2 Pharmacokinetic Parameters after Oral Intake of 20 mg THC Probands β (h -1 ) α (h -1 ) V c (L) t 0 (h) Ka (h -1 ) B% Smoking We have evaluated results of 6 studies which contain data relating to THC-levels in plasma after smoking of marijuana cigarettes with defined content of THC. The relevant data are demonstrated in Table 3. Included are the studies of Hollister et al. 1981, Chiang and Barnett 1984, Lindgren et al. 1981, Heishman et al. 1990, Huestis et al a, and Perez- Reyes et al Some studies although containing essential results were not considered for estimation of the means and standard deviations of pharmacokinetic parameters because they possess a too low number of data for differentiating between distribution and elimination phases (Möller et al. 1992) or the period of smoking was too long to assume an intake in points (McBurney et al. 1986). Only in some publications individual concentration-time curves are given. Because not all data are available in the several studies the number of probands must be different when calculating the pharmacokinetic parameters by us. Table 3 Pharmacokinetic Parameters after Smoking of Marijuana Cigarettes with Known Content of THC (derived from 6 studies with average value curves e.g. individual concentration-time curves) Probands Mean SD elimination constant β (h -1 ) distribution constant a (h -1 ) central distribution volume Vc(L) lag time t 0 (h) resorption constant Ka (h -1 ) bioavailability B (%) (at V d = 236 L) The constant of distribution in this collective is higher than after oral intake but still lower than after THC was applicated intravenously. The constant of elimination is between the data after oral and I.V. intake. The constant of resorption is - as it could be expected - much higher than after oral intake. 399

4 CONCLUSION For the calculation of pharmacokinetic parameters several valid data must be available. Only after I.V. injection the volume of distribution can be calculated. After oral intake or after smoking the bioavailability must be taken into account. Obviously the bioavailability is very poor after oral intake and very different after smoking. To calculate the distribution constant it is necessary in every case, that data in a very early phase after injection or smoking are available. At least 5 data in the first 30 minutes and additional 5 data between 60 and 240 minutes are necessary to calculate the distribution and elimination constants precisely. Most of the published studies do not fulfill these criteria and - in addition - they give not the measured individual concentrations but only average values. Nevertheless the pharmacokinetic parameters developed out of these studies under presumption of a two compartment model leads to a time plot of average THC-concentrations as well as minimum and maximum curves at which the standard deviation of the pharmacokinetic parameters are taken into account. In particular during resorption and in the late elimination stage estimation of plasma levels of THC is accompanied by a wide dispersion. Nevertheless estimation of THC-concentrations out of the amount of consumed marihuana at a stated time or on the other hand time interval out of THC-concentration in plasma is to be derived using the developed curves of THC-concentrations. After smoking of 20 mg THC through a person of 70 kg of body weight the following concentration ranges can be expected (Table 4). The range is much smaller than with the data achieved from model I of Huestis et al. (1992 b) because their data are independent from the dose and the body weight. In practise at least the body weight of a person involved in a traffic accident or suspected he had driven a motor vehicle under the influence of THC should be known. Table 4 Concentration ranges (ng/ml) at different times after smoking of THC. Our data are concerning a person of 70 kg of body weight and smoking of 20 mg THC. The data from Huestis et al. (1992 b) are independent from dose and body weight. t (h) This evaluation Huestis et al A correlation between the THC concentration in the serum and the main effects must be assumed. Then relevant effects on fitness to drive must be within the first 30 to 60 minutes after smoking a marijuana cigarette. If the government - as in Germany - is willing to punish a person when driving a motor vehicle within e.g. 4 hours after smoking THC, a limiting value of 8 ng THC/ml serum could be established. 400

5 REFERENCES Chiang, C.N., Barnett, G.: Marijuana effect and delta-9-tetrahydrocannabinol plasma level. Clin. Pharmacol. Ther. 36 (1984) Heishman, S.J., Huestis, M.A. Henningfield, J.E., Cone, E.J.: Acute and Residual Effects of Marijuana: Profiles of Plasma THC Levels, Physiological, Subjective, and Performance Measures. Pharmacology/Biochemistry and Behavior 37 (1990) Graß, H.: Computergestützte Analyse pharmakokinetischer Profile psychotroper Wirkstoffe unter besonderer Berücksichtigung rechtsmedizinischer Fragestellungen. Inaugural- Diss., Köln, 1989 Hollister, L.E., Gillespie, H.K., Ohlsson, A., Lindgren, J.-E., Wahlen, A., Agurell, S.: Do Plasma Concentrations of Delta-9-Tetrahydrocannabinol Reflect the Degree of Intoxication. J. Clin. Pharmacol. 2l(1981)171S-177S Huestis, M.A., Henningfield, J.E., Cone, E.J.: Blood Cannabinoids. I. Absorption of THC and Formation of 11-OH-THC and THCCOOH During and After Smoking Marijuana. J. Anal. Toxicol. 16 (1992 a) Huestis, M.A., Henningfield, J.E., Cone, E.J.: Blood Cannabinoids.II.Models for the prediction of time of marijuana exposure from plasma concentrations of A-9- tetrahydrocannabinol (THC) and 11-nor-9-carboxy-9-tetrahydrocannabinol (THCCOOH) J. Anal. Toxicol. 16 (1992 b) Hunt, A., Jones, R.T.: Tolerance and disposition of tetrahydrocannabinol in man. J. Pharmacol. Exp. Ther. 215 (1980) Käferstein, H., Sticht, G., Staak, M.: Psychotropically active substances and driving incapability - A pharmaco-kinetic computer model. In: M.W.Bud Perrine (ed.) Alcohol, drugs and traffic safety. National safety council (1990) Lindgren, J.E., Ohlsson, A., Agurell, S., Hollister, L., Gillespie, H.: Clinical effects and plasma levels of delta-9-tetrahydrocannabinol (delta-9-thc) in heavy and light users of cannabis. Psychopharmacol. 74 (1981) McBurney, L.J., Bobbie, B.A., Sepp, L.A.: GC/MS and EMIT Analyses for A-9- Tetrahydrocannabinol Metabolites in Plasma and Urine of Human Subjects. J. Anal. Toxicol. 10 (1986) Möller, M.R., Dörr, G., Warth, S.: Simultaneous Quantitation of Delta-9- tetrahydrocannabinol (THC) and 11 -Nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH) in Serum by GC/MS Using Deuterated Internal Standards and its Application to a Smoking Study and Forensic Cases. J. Forens. Sci. 37 (1992) Peat M.A. In: Advances in Analytical Toxicology, Vol. II. In: R.C. Baselt (ed.) Yearbook Medical Publishers, Chicago, 1989, pp Perez-Reyes, M., DiGuiseppi, S., Davis, K.H., Schindler, V., Cook, C.E.: Comparison of effects of marihuana cigarettes of three different potencies. Clin. Pharmacol. Ther. 31 (1982)

6 Sticht, G., Staak, M., Käferstein, H.: Die Ermittlung pharmakokinetischer Konstanten aus Wirkstoffspiegeln am Beispiel des Tetrazepam. In: Eisenmenger, W., Liebhardt, E., Schuck, M. (eds.) Festschrift für W. Spann (1986) Springer Verlag, Berlin Heidelberg New York 402