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Pharmacokinetic Determinants of Drug Abuse and Dependence

A Conceptual Perspective

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Summary

Drugs that produce physical dependence or have similar pharmacological profiles to highly abused drugs are unlikely to be considered acceptable for marketing. Thus, the prediction of abuse and dependence becomes an important issue in the development of new psychotropic drugs.

Both pharmacokinetic and non-pharmacokinetic factors play an important role in predicting dependence and abuse liability of drugs. Evidence for the importance of pharmacological factors includes: (a) the demonstration of drug binding to receptors of abused drugs; (b) tolerance; (c) ability to maintain self-administration; and (d) spontaneous or antagonist precipitated withdrawal. The pharmacokinetic properties that presumably contribute to persistent self-administration and abuse include rapid delivery of drug to the central nervous system (CNS), rapid absorption, low protein binding and high free drug clearance. The pharmacokinetic properties of a drug associated with dependence will include long half-life, low free drug clearance and presence of the drug in the body at high enough concentrations and for sufficient time to permit tolerance to develop.

These properties have important clinical implications for treatment and research in the area of abuse and dependence liability of psychoactive drugs.

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References

  • Alvin J, McHorse T, Hoyumpa A, Bush MT, Schenker D. The effect of liver disease in man on the disposition of phenobarbital. Journal of Pharmacology and Experimental Therapeutics 192: 224–235, 1975

    PubMed  CAS  Google Scholar 

  • Arendt RM, Greenblatt DJ, de Jong RH, Bonin JD, Abernethy DR, et al. In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution. Journal of Pharmacology and Experimental Therapeutics 227: 98–106, 1983

    PubMed  CAS  Google Scholar 

  • Armor DJ, Polich JM, Stambul HB. Alcoholism and treatment, Wiley, New York, 1978

    Google Scholar 

  • Babor TF, Mendelson JH, Gallant D, Kuehule JC. Interpersonal behaviour in group discussion during marijuana intoxication. International Journal of Addictions 13: 89–102, 1978

    CAS  Google Scholar 

  • Balter MB, Manheimer DI, Mellinger GD, Uhlenhuth EH. A cross-national comparison on antianxiety/sedative use. Current Medical Research and Opinion 8 (Suppl.): 5–20, 1984

    Article  PubMed  Google Scholar 

  • Berkowitz BA. The relationship of pharmacokinetics to pharmacological activity: Morphine, methadone and naloxone. Clinical Pharmacokinetics 1: 219–230, 1976

    Article  PubMed  CAS  Google Scholar 

  • Bigelow G, Griffiths RR, Liebson J. Experimental models for the modification of human drug self-administration. Methodological developments in the study of ethanol self-administration by humans. Federation Proceedings 34: 1785–1792, 1975

    PubMed  CAS  Google Scholar 

  • Boisse C, Okamoto M. Physical dependence to barbital compared to pentobarbital. IV. Influence of elimination kinetics. Journal of Pharmacology and Experimental Therapeutics 204: 526–540, 1978

    PubMed  CAS  Google Scholar 

  • Breimer DD, de Boer AG. Pharmacokinetics and relative bioavailability of heptabarbital and heptabarbital sodium after oral administration to man. European Journal of Clinical Pharmacology 9: 169–178, 1975

    Article  PubMed  CAS  Google Scholar 

  • Brodie BB, Kurz H, Schanker LS. The importance of dissociation constant and lipid-solubility in influencing the passage of drugs in the cerebrospinal fluid. Journal of Pharmacology and Experimental Therapeutics 130: 20–25, 1960

    PubMed  CAS  Google Scholar 

  • Brunk SF, Delle M. Morphine metabolism in man. Clinical Pharmacology and Therapeutics 16: 51–57, 1974

    PubMed  CAS  Google Scholar 

  • Busto U, Naranjo CA, Cappell HD, Simpkins J, Sanchez-Craig M, et al. Differences in patterns of benzodiazepine abuse. Proceedings II World Conference on Clinical Pharmacology and Therapeutics, Washington, D.C., August, 1983

  • Cappell H, LeBlanc AE. Tolerance to and physical dependence on ethanol. Why do we study them? Drugs and Alcohol Dependence 4: 15–31, 1979

    CAS  Google Scholar 

  • Chung M, Hilbert JM, Gural RP, Radwanski E, Synchowicz S, Sampaglione N. Multiple dose halazepam kinetics. Clinical Pharmacology and Therapeutics 35: 838–842, 1984

    Article  PubMed  CAS  Google Scholar 

  • Clay ML. Conditions affecting voluntary ethanol consumption. Quarterly Journal of Studies on Alcohol 25: 36–55, 1964

    PubMed  CAS  Google Scholar 

  • Einarson TR. Lorazepam withdrawal seizures. Lancet 1: 151, 1980

    Article  PubMed  CAS  Google Scholar 

  • Elliott HW, Parker PD, Wright JA, Nomof N. Actions and metabolism of heroin administered by continuous intravenous infusion to man. Clinical Pharmacology and Therapeutics 12: 806–814, 1971

    PubMed  CAS  Google Scholar 

  • Eriksson K. Alcohol inhibition and behaviour: A comparative genetic approach. In B. Eleftherious (Ed.) Plenum Press, New York, 1975

  • Eriksson K. Inherited metabolism and behaviour towards alcohol: critical evaluation of human and animal research. In Eriksson, Sinclair & Kiianmoa (Eds) Animal models in alcohol research, pp. 3–21, Academic Press, London, 1980

    Google Scholar 

  • Ewing JA, Bakewell WA. Diagnosis and management of depressant drug dependence. American Journal of Psychiatry 123: 909–917, 1967

    PubMed  CAS  Google Scholar 

  • Goodwin DW. The question of a genetic basis for alcoholism: A response. Quarterly Journal of Studies on Alcohol 34: 1345–1347, 1973

    Google Scholar 

  • Greenblatt DJ, Shader RI. Dependence, tolerance and addition to benzodiazepines: clinical and pharmacokinetic considerations. Drug Metabolism Reviews 8: 13–28, 1978

    Article  PubMed  CAS  Google Scholar 

  • Greenblatt DJ, Shader RI, Divoll M, Harmatz JS. Benzodiazepines: a summary of pharmacokinetic properites. British Journal of Clinical Pharmacology 11: 11S–16S, 1981

    Article  PubMed  CAS  Google Scholar 

  • Greenblatt DJ, Abernethy DR, Divoll M, Harmatz JS, Shader RI. Pharmacokinetic profile of benzodiazepine hypnotics. Journal of Clinical Psychopharmacology 3: 129–132, 1982

    Google Scholar 

  • Greenblatt DJ, Divoll M, Abernethy DR, Ochs HR, Shader RI. Clinical pharmacokinetics of the newer benzodiazepines. Clinical Pharmacokinetics 8: 233–252, 1983

    Article  PubMed  CAS  Google Scholar 

  • Griffiths RR, Stitzer M, Corber K, Bigelow GE, Liebson I. Drug produced changes in human social behaviour. Facilitation by d-amphetamine. Pharmacology Biochemistry and Behaviour 7: 365–372, 1977

    Article  CAS  Google Scholar 

  • Griffiths RR, Balster RL. Opioids: similarity between evaluation of subjective effects and animal self-administration results. Clinical Pharmacology and Therapeutics 25: 611–617, 1979

    PubMed  CAS  Google Scholar 

  • Griffiths RR, Bigelow GE, Henningfield JE. Similarities in animal and human drug taking behaviour. In N.K. Mellow (Ed.) Advances in substance abuse: behavioural and biological research, pp. 1–90, Jai Press, Greenwich, Connecticut, 1980

    Google Scholar 

  • Griffiths RR, Lukas SE, Bradford LDA, Brady JV, Snell JD. Self-injection of barbiturates and benzodiazepines in baboons. Psychopharmacology 75: 101–109, 1981

    Article  PubMed  CAS  Google Scholar 

  • Griffiths RR, MacLeod DR, Bigelow GE, Liebson LA, Roache JD, et al. Comparison of diazepam and oxazepam. Preference, liking and extent of abuse. Journal of Pharmacology and Experimental Therapeutics 229: 501–508, 1984

    PubMed  CAS  Google Scholar 

  • Hanna SM. A case of oxazepam dependence. British Journal of Psychiatry 120: 443–445, 1972

    Article  PubMed  CAS  Google Scholar 

  • Harrison M, Busto U, Naranjo CA, Kaplan HL, Sellers EM. Identification and detoxification of high dose benzodiazepine abusers. Clinical Pharmacology and Therapeutics 36: 527–533, 1984

    Article  PubMed  CAS  Google Scholar 

  • Hollister LE. Benzodiazepines 1980: a look at the issues. Psychosomatics 21 (Suppl. 1): 4–8, 1980

    PubMed  CAS  Google Scholar 

  • Inturrisi CE, Schultz M, Shin S, Umans JG, Angel L, Simon EJ. Evidence from opiate binding studies that heroin acts through its metabolites. Life Sciences 33: 773–776, 1983

    Article  PubMed  CAS  Google Scholar 

  • Jaffe JH, Circaulo DA, Nies A, Dixon RB, Monroe LL. Abuse potential of halazepam and of diazepam in patients recently treated for acute alcohol withdrawal. Clinical Pharmacology and Therapeutics 34: 623–630, 1983

    Article  PubMed  CAS  Google Scholar 

  • Jasinki DR. Assessment of the abuse potentiality of morphinelike drugs (methods used in man). In W.R. Martin (Ed.) Drug addiction I, pp. 197–258, Springer Verlag, New York, 1977

    Chapter  Google Scholar 

  • Johanson CE, Schuster CR. Procedures for the pre-clinical assessment of abuse potential of psychotropic drugs in animals. In T. Thompson & K. Unna (Eds) Predicting dependence liability of stimulant and depressant drugs, pp. 203–231, University Park Press, Baltimore, 1977

    Google Scholar 

  • Johanson CE, Balster RL. A summary of the results of a drug self-administration study using substitution procedures in rhesus monkeys. Bulletin on Narcotics 30: 43–54, 1978

    PubMed  CAS  Google Scholar 

  • Johanson CE, Schuster CR. Animal models of drug self-administration. In N.K. Mello (Ed.) Advances in substance abuse: behavioural and biological research, Jai Press, Greenwich, Connecticut, 1981

    Google Scholar 

  • Kalant H, Le Blanc AE, Gibbins RJ. Tolerance to, and dependence on, some nonopiate psychotropic drugs. Pharmacology Review 23: 135–191, 1971

    CAS  Google Scholar 

  • Martin PR, Kapur BM, Whiteside EA, Sellers EM. Intravenous phenobarbital therapy and other hypnosedative withdrawal reactions: a kinetic approach. Clinical Pharmacology and Therapeutics 26: 256–264, 1979

    PubMed  CAS  Google Scholar 

  • Meisch RA, Thompson T. Ethanol intake as a function of concentration during food deprivation and satiation. Pharmacology Biochemistry and Behaviour 2: 589–596, 1975

    Article  Google Scholar 

  • Myers AKJ. Alcohol choice in Wistar and G-4 rats as a function of environmental temperature and alcohol concentration. Journal of Comparative Physiological Psychology 55: 606–609, 1962

    Article  CAS  Google Scholar 

  • Nichols JR. How opiates change behaviour. Scientific American 212: 80–88, 1965

    Article  PubMed  CAS  Google Scholar 

  • Pickens R, Thompson T. Self-administration of amphetamines and cocaine by rats. 29th Annual Meeting of the Committee on Problems of Drug Dependence, NAS-NRC, 1967

    Google Scholar 

  • Proudfoot AT, Park J. Changing patterns of drugs used for self-poisoning. British Medical Journal 1: 90–93, 1978

    Article  PubMed  CAS  Google Scholar 

  • Ramsey RE, Hammond EJ, Perchalsky RJ, Wilder BJ. Brain uptake of Phenytoin, phenobarbital and diazepam. Archives of Neurology 36: 535–539, 1979

    Article  Google Scholar 

  • Robinson GM, Sellers EM, Janecek E. Barbiturate and hypnosedative withdrawal by a multiple oral phenobarbital loading dose. Clinical Pharmacology and Therapeutics 30: 71–76, 1981

    Article  PubMed  CAS  Google Scholar 

  • Schuckit MA, Vidamantas R. Ethanol ingestion: Differences in blood acetaldehyde concentrations in relatives of alcoholics and controls. Science 203: 54–55, 1979

    Article  PubMed  CAS  Google Scholar 

  • Schuster GR, Thompson T. Self-administration of and behavioural dependence on drugs. Annual Review of Pharmacology 9: 483–502, 1969

    Article  PubMed  CAS  Google Scholar 

  • Sellers EM. Addictive drugs: disposition, tolerance and dependence interrelationships. Drug Metabolism Reviews 8: 5–11, 1978

    Article  PubMed  CAS  Google Scholar 

  • Sellers EM, Holloway MR. Drug kinetics and alcohol ingestion. Clinical Pharmacokinetics 3: 440–452, 1978

    Article  PubMed  CAS  Google Scholar 

  • Sellers EM, Marshman JA, Kaplan HL, Giles HG, Kapur BM, et al. Acute and chronic drug abuse emergencies in Metropolitan Toronto. International Journal of Addictions 16: 283, 1981

    CAS  Google Scholar 

  • Smith RB, Dittert LW, Griffen WO, Doluisio JT. Pharmacokinetics of pentobarbital after intravenous and oral administration. Journal of Pharmacokinetics and Biopharmaceutics 1: 5–16, 1973

    CAS  Google Scholar 

  • Stitzer ML, Griffiths RR, McLellan AT, Grabowski J, Hawthorne JW. Diazepam use among methadone maintenance patients: patterns and dosage. Drug and Alcohol Dependence 8: 189–199, 1981

    Article  PubMed  CAS  Google Scholar 

  • Way EL, Adler TK. The pharmacological implications of the fate of morphine its surrogates. Pharmacological Reviews 12: 383–446, 1960

    PubMed  CAS  Google Scholar 

  • Weeks JR. Experimental morphine addiction: method for autonomic intravenous injections in urestrained rats. Science 138: 143–144, 1962

    Article  PubMed  CAS  Google Scholar 

  • Winger G, Stitzer ML, Woods JH. Barbiturate-reinforced responding in rhesus monkeys: comparisons of drugs with different durations of action. Journal of Pharmacology and Experimental Therapeutics 195: 504–514, 1975

    Google Scholar 

  • Woods JH, Schuster CR. Reinforcement properties of morphine, cocaine and SPA as a function of unit dose. International Journal of Addictions 3: 231–237, 1968

    Google Scholar 

  • World Health Organization, Technical Report Series No. 407, 1969

  • World Health Organization, Sixth Review of Psychoactive Substances for International Control, Geneva, 1982

    Google Scholar 

  • World Health Organization, Eighth Review of Psychoactive Substances for International Control, Geneva, 1983

    Google Scholar 

  • Yanagita T, Takahashi S. Dependence liability of several sedative-hypnotics evaluated in monkeys. Journal of Pharmacology and Experimental Therapeutics 185: 307–316, 1973

    PubMed  CAS  Google Scholar 

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Busto, U., Sellers, E.M. Pharmacokinetic Determinants of Drug Abuse and Dependence. Clin-Pharmacokinet 11, 144–153 (1986). https://doi.org/10.2165/00003088-198611020-00004

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