Modelling of the concentration—effect relationship of THC on central nervous system parameters and heart rate — insight into its mechanisms of action and a tool for clinical research and development of cannabinoids
Restricted accessOtherFirst published online September, 2008
Modelling of the concentration—effect relationship of THC on central nervous system parameters and heart rate — insight into its mechanisms of action and a tool for clinical research and development of cannabinoids
Pharmacokinetics after pulmonary administration of δ-9-tetrahydrocannabinol (THC) and its major metabolites 11-OH-THC and 11-nor-9-COOH-THC was quantified. Additionally, the relationship between THC and its effects on heart rate, body sway and several visual analogue scales was investigated using pharmacokinetic—pharmacodynamic (PK-PD) modelling. This provided insights useful for the research and development of novel cannabinoids and the physiology and pharmacology of cannabinoid systems. First, the PK-PD model gave information reflecting various aspects of cannabinoid systems. The delay between THC concentration and effect was quantified in equilibration half-lives of 7.68 min for heart rate and from 39.2 to 84.8 min for the CNS responses. This suggests that the effect of THC on the different responses could be due to different sites of action or different physiological mechanisms. Differences in the shape of the concentration—effect relationship could indicate various underlying mechanisms. Second, the PK-PD model can be used for prediction of THC concentration and effect profiles. It is illustrated how this can be used to optimise studies with entirely different trial designs. Third, many new cannabinoid agonists and antagonists are in development. PK-PD models for THC can be used as a reference for new agonists or as tools to quantitate the pharmacological properties of cannabinoid antagonists.
Aarons, L., Karlsson, M., Mentre, F., Rombout, F., Steimer, JL, van Peer, A. ; COST B15 Experts (2001) Role of modelling and simulation in phase I drug development. J Pharmacokinet Pharmacodyn31: 419-440.
2.
Ameri, A. (1999) The effects of cannabinoids on the brain. Prog Neurobiol58: 315-348.
3.
Barnett, G., Chiang, CW, Perez-Reyes, M., Owens, SM (1982) Kinetic study of smoking marijuana. J Pharmacokinet Biopharm10: 495- 506.
Bond, A., Lader, M. (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol47: 211-218.
6.
Bonz, A., Laser, M., Kullmer, S., Kullmer, S., Kniesch, S., Babin-Ebell, J., Popp, V., Ertl, G., Wagner, JA (2003) Cannabinoids acting on CB1 receptors decrease contractile performance in human atrial muscle. J Cardiovasc Pharmacol41: 657-664.
7.
Breimer, DD, Danhof, M. (1997) Relevance of the application of pharmacokinetic-pharmacodynamic modelling concepts in drug development. The `wooden shoe' paradigm. Clin Pharmacokinet32: 259-267.
8.
Chiang, CW, Barnett, G. (1984) Marijuana effect and delta-9-tetrahydrocannabinol plasma level. Clin Pharmacol Ther36: 234-238.
9.
Chiang, CN, Rapaka, RS (1987) Pharmacokinetics and disposition of cannabinoids . NIDA Res Monogr79: 173-188.
10.
Ebert, U., Kirch, W. (1998) Scopolamine model of dementia: electroencephalogram findings and cognitive performance. Eur J Clin Invest28: 944-949.
11.
Fuseau, E., Sheiner, LB (1984) Simultaneous modeling of pharmacokinetics and pharmacodynamics with a nonparametric pharmacodynamic model. Clin Pharmacol Therapeut35: 733-741.
12.
Gijsman, HJ, Cohen, AF, Van Gerven, JMA (2004) The application of the principles of clinical drug development to pharmacological challenge tests of the serotonergic system . J Psychopharmacol18: 7-13.
13.
Grotenhermen, F. (2003) Pharmacokinetics and pharmacodynamics of cannabinoids . Clin Pharmacokinet42: 327-360.
14.
Harder, S., Rietbrock, S. (1997) Concentration-effect relationship of delta-9-tetrahydrocannabiol and prediction of psychotropic effects after smoking marijuana. Int J Clin Pharmacol Ther35: 155-159.
15.
Holford, NH, Sheiner, LB (1981) Pharmacokinetic and pharmacodynamic modeling in vivo. Crit Rev Bioeng5: 273-322.
16.
Howlett, AC, Breivogel, CS, Childers, SR, Deadwyler, SA, Hampson, RE, Porrino, LJ (2004) Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology47(Suppl. 1): 345- 358.
17.
Huestis, MA, Gorelick, DA, Heishman, SJ, Preston, KL, Nelson, RA, Moolchan, ET, Frank, RA (2001) Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry58: 322-328.
18.
Jacqmin, P., Snoeck, E., van Schaick, EA, Gieschke, R., Pillai, P., Steimer, JL, Girard, P. (2007) Modelling response time profiles in the absence of drug concentrations: Definition and performance evaluation of the K-PD model. J Pharmacokinet Pharmacodyn34: 57-85.
19.
Jonker, DM, Visser, SA, van der Graaf, PH, Voskuyl, RA, Danhof, M. (2005) Towards a mechanism-based analysis of pharmacodynamic drug-drug interactions in vivo. Pharmacol Ther106: 1-18.
20.
Le Foll, B., Goldberg, SR (2005) Cannabinoid CB1 antagonists as promising new medications for drug dependence. J Pharmacol Exp Ther312: 875-883.
21.
Mukhopadhyay, S., Howlett, AC (2001) CB1 receptor-G protein association. Subtype selectivity is determined by distinct intracellular domains. Eur J Biochem268: 499-505.
22.
Netter, P. (2006) Dopamine challenge tests as an indicator of psychological traits. Hum Psychopharmacol21: 91-99.
23.
Ohlsson, A., Lindgren, JE, Wahlen, A., Agurell, S., Hollister, LE, Gillespie, HK (1980) Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking . Clin Pharmacol. Ther28: 409-416.
24.
Perez-Reyes, M., Timmons, MC, Lipton, MA, Davis, KH, Wall, ME (1972) Intravenous injection in man of 9 -tetrahydrocannabinol and 11-OH- 9 -tetrahydrocannabinol. Science177: 633-635.
25.
Pertwee, RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors . Pharmacol Ther74: 129-180.
26.
Prather, PL, Martin, NA, Breivogel, CS, Childers, SR (2000) Activation of cannabinoid receptors in rat brain by WIN 55212-2 produces coupling to multiple G protein alpha-subunits with different potencies. Mol Pharmacol57: 1000-1010.
27.
Randall, MD, Harris, D., Kendall, DA, Ralevic, V. (2002) Cardiovascular effects of cannabinoids. Pharmacol Ther95: 191-202.
28.
Schoemaker, RC, Cohen, AF (1996) Estimating impossible curves using NONMEM. Br J Clin Pharmacol42: 283-290.
29.
Steveninck, ALV, Schoemaker, HC, Hartigh, JD, Pieters, MSM, Breimer, DD, Cohen, AF (1994) Effects of intravenous temazepam. II. A study of the long-term reproducibility of pharmacokinetics, pharmacodynamics, and concentration-effect parameters. Clin Pharmacol Ther55: 546-555.
30.
Van der Does, AJ (2001) The effects of tryptophan depletion on mood and psychiatric symptoms. J Affect Disord64: 107-119.
31.
Van der Post, JP, de Visser, SJ, Schoemaker, RC, Cohen, AF, van Gerven, JM (2004) Pharmacokinetic/pharmacodynamic assessment of tolerance to central nervous system effects of a 3 mg sustained release tablet of rilmenidine in hypertensive patients. J Psychopharmacol18: 221-227.
32.
Wall, ME, Perez-Reyes, M. (1981) The metabolism of delta-9-tetrahydrocannabinol and related cannabinoids in man. J Clin Pharmacol21(Suppl. 8-9): 178S-189S.
33.
Wall, ME, Sadler, BM, Brine, D., Taylor, H., Perez-Reyes, M. (1983) Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women. Clin Pharmacol Ther34: 352-363.
34.
Widman, M., Nordqvist, M., Agurell, S., Lindgren, JE, Sandberg, F. (1974) Biliary excretion of delta1-tetrahydrocannabinol and its metabolites in the rat. Biochem Pharmacol23: 1163-1172.
35.
Wright, BM (1971) A simple mechanical ataxia-meter. J Physiol218: 27P-28P.
36.
Zuurman, L., Roy, C., Schoemaker, RC, Hazekamp, A., den Hartigh, J., Bender, Jcme, Verpoorte, R., Pinquier, J-L., Cohen, AF, van Gerven, JMA (2008) Effect of intrapulmonary THC administration in humans. J Psychopharmacol (companion article).
