Summary
The elderly frequently use psychoactive drugs including alcohol (ethanol), benzodiazepines and opioid analgesics, which have a propensity to cause abuse and dependence. Theoretically, the changes in pharmacokinetics of these agents in the elderly may modify their abuse and dependence potential. In the elderly, blood alcohol concentrations following an oral dose are higher, alcohol withdrawal syndrome follows a more severe and protracted clinical course and requires treatment with higher doses of chlordiazepoxide than needed for younger adults. However, there is no direct evidence that supports an increased direct abuse and dependence potential of alcohol because of its altered kinetics in the elderly.
In the case of oxidatively metabolised benzodiazepines, both age-related pharmacokinetic and pharmacodynamic changes may increase their clinical effects in the elderly. The hypothesis that benzodiazepines have an increased abuse and dependence potential in the elderly has not been tested. Many of the benzodiazepines (e.g. alprazolam, triazolam and midazolam) are metabolised by the cytochrome P450 (CYP) 3A subfamily. The pharmacokinetics of these agents may be modified by inhibition of CYP3A due to concurrently administered medications such as selective serotonin reuptake inhibitors. Unfortunately, data on the direct measures of abuse and dependence potential of benzodiazepines are not available in the elderly. Thus, a conclusive statement on the contribution of age-related pharmacokinetic changes to benzodiazepine abuse and dependence cannot be made at the present time.
The clinical effects of codeine do not appear to change with age. Codeine is O-demethylated to its active metabolite morphine by the genetically polymorphic CYP2D6 isozyme. The activity of this isozyme is unaltered by age, gender or smoking habits; however, it is subject to potent inhibition by some of the frequently used medications in the elderly, such as the antidepressants paroxetine and fluoxetine. This may result in an impairment in O-demethylation of codeine to morphine and may lead to a decrease in the abuse and dependence potential of codeine. Conversely, those with a very rapid CYP2D6 catalytic activity may have an increased potential for codeine abuse and dependence.
The clinical significance of age-related pharmacokinetic changes should be evaluated within the context of clinical practice. Most physicians are inclined to prescribe lower doses to the elderly, which may offset the potential impact of altered pharmacokinetics on the abuse and dependence potential of psychoactive agents.
Insummary, the available data are not sufficient for a definitive conclusion on whether the pharmacokinetic changes in the elderly translate to an increase in the abuse and dependence potential of alcohol, benzodiazepines or opioids. In particular, the data on age-associated changes in direct measures of abuse potential of these agents are missing. Future comparative systematic pharmacokinetic-pharmacodynamic studies assessing pertinent outcome measures on abuse and dependence potential of commonly used psychoactive drugs are required to resolve the ongoing controversy on risk factors for drug abuse and dependence in the elderly.
Similar content being viewed by others
References
Naranjo CA, Herrmann N, Özdemir V, et al. Abuse of prescription and licit psychoactive substances by the elderly: issues and recommendations. CNS Drugs 1995; 4(3): 207–21
The use of alcohol and other drugs by older Canadians and its consequences. Catalogue No. H39-259/1992E. Ottawa: Health and Welfare Canada, 1992
Simons LA, Tett S, Simons J, et al. Multiple medication use in the elderly: use of prescription and non-prescription drugs in an Australian community setting. Med J Aust 1992; 157: 242–6
Shorr RI, Bauwens SF, Landefeld CS. Failure to limit quantities of benzodiazepine hypnotic drugs for outpatients: placing the elderly at risk. Am J Med 1990; 89: 725–32
Mant A, Duncan-Jones P, Saltman D, et al. Development of long term use of psychotropic drugs by general practice patients. BMJ 1988; 296: 251–4
Morgan K, Dallosso H, Ebrahim S, et al. Prevalence, frequency and duration of hypnotic use among the elderly living at home. BMJ 1988; 296: 601–2
Woods JH, Katz JL, Winger G. Use and abuse of benzodiazepines: issues relevant to prescribing. JAMA 1988; 260: 3476–80
Koenig W, Ruther E, Filipiak B. Psychotropic drug utilization patterns in a metropolitan population. Eur J Clin Pharmacol 1987; 32: 43–51
Woods JH, Katz JL, Winger G. Abuse liability of benzodiazepines. Pharmacol Rev 1987; 39: 251–413
Glynn RJ, Bouchard GR, LoCastro JS, et al. Aging and generational effects on drinking behaviors in men: results from the normative aging study. Am J Public Health 1985; 75: 1413–9
Mellinger GD, Balter MB, Uhlenhuth EH. Insomnia and its treatment: prevalence and correlates. Arch Gen Psychiatry 1985; 42: 225–32
Morgan K. Sedative-hypnotic drug use and ageing. Arch Gerontol Geriatr 1983; 2: 181–99
Salzman C, Fisher J, Nobel K, et al. Cognitive improvement following benzodiazepine discontinuation in elderly nursing home residents. Int J Geriatr Psychiatry 1992; 7: 89–93
Kruse WHH. Problems and pitfalls in the use of benzodiazepines in the elderly. Drug Saf 1990; 5: 328–44
Sorock GS, Shimkin EE. Benzodiazepine sedatives and the risk of falling in a community-dwelling elderly cohort. Arch Intern Med 1988; 148: 2441–4
Tinetti ME, Speechley M, Ginter SF. Risk factors for falls among the elderly persons living in the community. N Engl J Med 1988; 319: 1701–7
Larson EB, Kukull WA, Buchner DA, et al. Adverse drug reactions associated with global cognitive impairment in elderly persons. Ann Intern Med 1987; 107: 169–73
Ray W, Griffin M, Schaffner W, et al. Psychotropic drug use and the risk of hip fracture. N Engl J Med 1987; 316: 363–9
Greenblatt DJ, Allen MD. Toxicity of nitrazepam in the elderly: a report from the Boston Collaborative Drug Surveillance Program. Br J Clin Pharmacol 1978; 5: 407–13
Greenblatt DJ, Allen MD, Shader RI. Toxicity of high-dose flurazepam in the elderly. Clin Pharmacol Ther 1977; 21: 355–61
Busto UE, Lanctot KL, Bremner KE. et al. Benzodiazepine kinetics contribute to their differential abuse. Can J Clin Pharmacol 1995; 2(1): 23–28
Naranjo CA, Busto UE. Dose response relationships in drug dependence in humans. In: Lasagna L, Erill S, Naranjo CA, editors. Dose-response relationships in clinical pharmacology. Amsterdam: Elsevier Science Publishers Biomedical Division, 1989: 79–92
Sellers EM, Busto U, Kaplan HL. Pharmacokinetic and pharmacodynamic drug interactions: implications for abuse liability testing. In: Fishman MW, Mello NK, editors. Testing for abuse liability of drugs. NIDA Res Monogr 1989; 92: 287–306
Busto U, Sellers EM. Pharmacokinetic determinants of drug abuse and dependence: a conceptual perspective. Clin Pharmacokinet 1986; 11: 144–53
Higuchi S, Matsushita S, Murayama M, et al. Alcohol and aldehyde dehydrogenase polymorphisms and the risk for alcoholism. Am J Psychiatry 1995; 152: 1219–21
Shen WW. Cytochrome P450 monooxygenases and interactions of psychotropic drugs: a five-year update. Int J Psychiatry Med 1995; 25(3): 277–90
Von Moltke LL, Greenblatt DJ, Schmider J, et al. Metabolism of drugs by cytochrome P450 3A isoforms: implications for drug interactions in psychopharmacology. Clin Pharmacokinet 1995; 29 Suppl. 1: 33–44
Robin DW, Lee M, Hasan SS, et al. Triazolam in cirrhosis: pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 1993; 54: 630–7
Cholerton S, Daly AK, Idle JR. The role of individual human cytochromes P450 in drug metabolism and clinical response. Trends Pharmacol Sci 1992; 13: 434–9
Murray M. P450 enzymes: Inhibition mechanisms, genetic regulation and effects of liver disease. Clin Pharmacokinet 1992; 23: 132–46
Durnas C, Loi C, Cusack BJ. Hepatic drug metabolism and aging. Clin Pharmacokinet 1990; 19: 359–89
Vestal RE. Aging and determinants of hepatic drug clearance. Hepatology 1989; 9: 331–4
Farrell GC. Drug metabolism in extrahepatic diseases. Pharmacol Ther 1987; 35: 375–404
Teng YS. Human liver aldehyde dehydrogenase in Chinese and Asiatic Indians: gene detection and the possible implication in alcohol metabolism. Biochem Genet 1981; 19: 107–13
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994
Shader RI, Greenblatt DJ. Use of benzodiazepines in anxiety disorders. N Engl J Med 1993; 328: 1398–405
Woolverton WL, Wessinger WD, Balster RL. Reinforcing properties of clonidine in rhesus monkeys. Psychopharmacology 1982; 77: 17–23
Meyer DR, El-Azhary R, Bierer DWS, et al. Tolerance and dependence after chronic administration of clonidine to the rat. Pharmacol Biochem Behav 1977; 7: 227–31
Winger GD, Stitzer M, Woods JH. Barbiturate-reinforced responding in rhesus monkeys: comparison of drugs with different durations of actions. J Pharmacol Exp Ther 1975; 195: 505–14
Greenblatt DJ, Harmatz JS, Shader RI. Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly: therapeutic considerations (Pt I). Clin Pharmacokinet 1991; 21: 165–77
Greenblatt DJ, Harmatz JS, Shader RI. Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly: therapeutic considerations (Pt II). Clin Pharmacokinet 1991; 21: 262–273
Davies KN, Castleden CM, McBurney A, et al. The effect of ageing on the pharmacokinetics of dihydrocodeine. Eur J Clin Pharmacol 1989; 37: 375–9
Owen JA, Sitar DS, Berger L, et al. Age-related morphine kinetics. Clin Pharmacol Ther 1983; 34: 364–8
Pozzato G, Moretti M, Franzin F, et al. Ethanol metabolism and aging: the role of ‘first pass metabolism’ and gastric alcohol dehydrogenase activity. J Gerontol 1995; 50A(3): B135–41
Vestal RE, McGuire EA, Tobin JD, et al. Aging and ethanol metabolism. Clin Pharmacol Ther 1976; 21: 343–54
Busto U, Lanctot KL, Isaac P, et al. Benzodiazepine use and abuse in Canada. Can Med Assoc J 1989; 141: 917–21
Gurwitz JH, Avorn J. The ambiguous relation between aging and adverse drug reactions. Ann Intern Med 1991; 114: 956–966
Greenblatt DJ, Shader RI, Harmatz JS. Implications of altered drug disposition in the elderly: studies of benzodiazepines. J Clin Pharmacol 1989; 29: 866–72
Rodrigo EK, King MB, Williams P. Health of long term benzodiazepine users. BMJ 1988; 296: 603–6
Shader RI, Greenblatt DJ. Benzodiazepine overuse-misuse. J Clin Psychopharmacol 1984; 4: 123–4
Greenblatt DJ, Harmatz JS, Shapiro L, et al. Sensitivity to triazolam in the elderly. N Engl J Med 1991; 324: 1691–8
Ammon E, Schafer C, Hofmann U, et al. Disposition and first-pass metabolism of ethanol in humans: is it gastric or hepatic and does it depend on gender? Clin Pharmacol Ther 1996; 59: 503–13
Wagner JG. Intrasubject variation in elimination half-lives of drugs which are appreciably metabolized. J Pharmacokinet Biopharm 1973; 1: 165–73
Liskow BI, Rinck C, Campbell J. Alcohol withdrawal in the elderly. J Stud Alcohol 1989; 50: 414–21
Shibuya A, Yoshida A. Frequency of the atypical aldehyde de-hydrogenase-2 gene (ALDH2) in Japanese and Caucasians. Am J Hum Genet 1988; 43: 741–3
Brien JF, Loomis CW. Aldehyde dehydrogenase inhibitors as alcohol-sensitizing drugs: a pharmacological perspective. Trends Pharmacol Sci 1985; 6: 478–80
Thomasson HR, Edenberg HJ, Crabb DW, et al. Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am J Hum Genet 1991; 48: 677–81
Hawley CJ, Tattersall M, Dellaportas C, et al. Comparison of long-term benzodiazepine users in three settings. Br J Psychiatry 1994; 165: 792–6
Balter MB, Manheimer DI, Mellinger GD, et al. A cross-national comparison of anti-anxiety/sedative drug use. Curr Med Res Opin 1984; 8 Suppl. 4: 5–20
Barnhill JG, Greenblatt DJ, Miller LG, et al. Kinetic and dynamic components of increased benzodiazepine sensitivity in aging animals. J Pharmacol Exp Ther 1990; 253: 1153–61
Cook PJ, Flanagan R, James IM. Diazepam tolerance: effect of age, regular sedation, and alcohol. BMJ 1984; 289: 351–3
Swift CG, Ewen JM, Clarke P, et al. Responsiveness to oral diazepam in the elderly: relationship to total and free plasma concentrations. Br J Clin Pharmacol 1985; 20: 111–8
Suhara T, Inoue O, Kobayashi K, et al. No age-related changes in human benzodiazepine receptor binding measured by PET with [11C]Ro 15-4513. Neurosci Lett 1993; 159: 207–10
Evans SM, Critchfield TS, Griffiths RR. Abuse liability assessment of anxiolytics/hypnotics: rationale and laboratory core. Br J Addict 1991; 86: 1625–32
Fischman MW, Foltin RW. Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. Br J Addict 1991; 86: 1563–70
Jasinski DR, Johnson RE, Henningfield JE. Abuse liability assessment in human subjects. Trends Pharmacol Sci 1984; 5: 196–200
Johanson CE, Uhlenhuth EH. Drug preference and mood in humans: diazepam. Psychopharmacology 1980; 71: 269–73
De Wit H, Johanson CE, Uhlenhuth EH. The dependence potential of benzodiazepines. Curr Med Res Opin 1984; 8: 48–59
De Wit H, Uhlenhuth EH, Johanson CE. Lack of preference for flurazepam in normal volunteers. Pharmacol Biochem Behav 1984; 21: 865–9
De Wit H, Uhlenhuth EH, Hedeker D. Lack of preference for diazepam in anxious volunteers. Arch Gen Psychiatry 1986; 43: 533–41
Griffiths RR, Bigelow G, Liebson I. Human drug self-administration: double-blind comparison of pentobarbital, diazepam, chlorpromazine and placebo. J Pharmacol Exp Ther 1979; 210: 301–10
Griffiths RR, Bigelow GE, Liebson I, et al. Drug preference in humans: double-blind comparison of pentobarbital, diazepam, and placebo. J Pharmacol Exp Ther 1980; 215: 649–61
Griffiths RR, McLeod DR, Bigelow GE, et al. Comparison of diazepam and oxazepam: preference, liking and extent of abuse. J Pharmacol Exp Ther 1984; 229: 501–8
Pollock BG, Perel JM, Altieri LP, et al. Debrisoquine hydroxylation phenotyping in geriatric psychopharmacology. Psychopharmacol Bull 1992; 28: 163–8
Schmucker DL, Woodhouse KW, Wang RK, et al. Effects of age and gender on in vitro properties of human liver microsomal monooxygenases. Clin Pharmacol Ther 1990; 48: 365–74
Wynne HA, Mutch E, James OFW, et al. The effect of age upon the affinity of microsomal monooxygenase enzymes for substrate in human liver. Age Ageing 1988; 17: 401–5
Schmucker DL. Aging and drug disposition: an update. Pharmacol Rev 1985; 37: 133–48
Woodhouse KW, Mutch E, Williams FM, et al. The effect of age on pathways of drug metabolism in human liver. Age Ageing 1984; 13: 328–34
Nemeroff CB, DeVane CL, Pollock BG. Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996; 153(3): 311–20
Rasmussen BB, Maenpaa J, Pelkonen O, et al. Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine. Br J Clin Pharmacol 1995; 39(2): 151–9
von Moltke LL, Greenblatt DJ, Court MH, et al. Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Psychopharmacol 1995; 15: 125–31
Fleishaker JC, Hulst LK. A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine. Eur J Clin Pharmacol 1994; 46: 35–9
Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 56: 601–7
Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 56: 601–7
von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, et al. Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants, ketoconazole and quinidine. Br J Clin Pharmacol 1994; 38: 23–31
Brosen K, Hansen JG, Nielsen KK, et al. Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 1993; 44: 349–55
Gillum JG, Israel DS, Polk RE. Pharmacokinetic drug interactions with antimicrobial agents. Clin Pharmacokinet 1993; 25: 450–82
Otton VS, Dafang W, Russell TJ, et al. Inhibition by fluoxetine of cytochrome P450 2D6 activity. Clin Pharmacol Ther 1993; 53: 401–9
Crewe HK, Lennard MS, Tucker GT, et al. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 1992; 34: 262–5
Greenblatt DJ, Preskorn SH, Cotreau MM, et al. Fluoxetine impairs clearance of alprazolam but not of clonazepam. Clin Pharmacol Ther 1992; 52: 470–86
Lasher TA, Fleishaker JC, Steenwyk RC, et al. Pharmacokinetic pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine. Psychopharmacology 1991; 104: 323–7
Kronbach T, Mathys D, Umeno M, et al. Oxidation of midazolam and triazalom by human liver cytochrome P450IIIA 4. Mol Pharmacol 1989; 36: 89–96
Bertilsson L, Henthorn TK, Sanz E, et al. Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin but not debrisoquine hydroxylation pheno-type. Clin Pharmacol Ther 1989; 45: 348–55
Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994; 270: 414–23
Bertilsson L, Lou YQ, Du YL, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquine and S-mephenytoin. Clin Pharmacol Ther 1992; 51: 388–97
Jurima M, Inaba T, Kadar D, et al. Genetic polymorphism of mephenytoin p (4′)-hydroxylation: difference between Orientals and Caucasians. Br J Clin Pharmacol 1985; 19: 483–7
Nakamura K, Goto F, Ray WA, et al. Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol 1985; 38: 402–8
Crowley JJ, Cusack BJ, Jue SG, et al. Induction of theophylline metabolism by phenytoin is unaltered by aging. Clin Res 1986; 34: 396A
Twum-Barima Y, Finnigan T, Habash AI, et al. Impaired enzyme induction by rifampicin in the elderly. Br J Clin Pharmacol 1984; 17: 595–6
Cusack BJ, Kelly JG, Lavan J, et al. Theophylline kinetics in relation to age: The importance of smoking. Br J Clin Pharmacol 1980; 10: 109–14
Mucklow JC, Fraser HS. The effects of age and smoking upon antipyrine metabolism. Br J Clin Pharmacol 1980; 9: 63–4
Salem SAM, Rajjayabun P, Shepherd AMM, et al. Reduced induction of drug metabolism in the elderly. Age Ageing 1978; 7: 68–73
Vestal RE, Norris AH, Tobin JD, et al. Antipyrine metabolism in man: influence of age, alcohol, caffeine and smoking. Clin Pharmacol Ther 1975; 18: 425–32
Bigelow GE. Human drug abuse liability assessment: opioids and analgesics. Br J Addict 1991; 86: 1615–28
Adler TK, Fujimoto JM, Way EL, et al. The metabolic fate of codeine in man. J Pharmacol Exp Ther 1955; 114: 251–62
Yue QY, Svensson JO, Alm C, et al. Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. Br J Clin Pharmacol 1989; 28: 639–45
Chen ZR, Somogyi AA, Bochner F. Polymorphic O-demethylation of codeine. Lancet 1988; 2: 914–5
Guay DRP, Awni WM, Findlay JWA, et al. Pharmacokinetics and pharmacodynamics of codeine in end-stage renal disease. Clin Pharmacol Ther 1988; 43: 63–71
Yue QY, Hasselström J, Svensson JO, et al. Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine. Br J Clin Pharmacol 1991; 31: 635–42
Paul D, Standifer KM, Inturrisi CE, et al. Pharmacological characterization of morphine-6β-glucuronide, a very potent morphine metabolite. J Pharmacol Exp Ther 1989; 251: 477–83
Quiding H, Anderson P, Bondesson U, et al. Plasma concentrations of codeine and its metabolite, morphine, after single and repeated oral administration. Eur J Clin Pharmacol 1986; 30: 673–7
Sanfilippo G. Contributo sperimentale all’ipotesi della smetilazione della codeina nell’organismo: I. Influenze della dose sull’assuefazione alla codeina. II. Assuefazione alla codeina attenuta con somministrazione prolungata di morfina. Boll Soc Ital Biol Sper 1948; 24: 723–6
Persson K, Sjöstrom S, Sigurdardottir I, et al. Patient-controlled analgesia (PCA) with codeine for postoperative pain relief in ten extensive metabolisers and one poor metaboliser of dextromethorphan. Br J Clin Pharmacol 1995; 39: 182–6
Desmeules J, Gascon MP, Dayer P, et al. Impact of environmental and genetic factors on codeine analgesia. Eur J Clin Pharmacol 1991; 41: 23–6
Irvine RJ, Chen ZR, Somogyi AA, et al. μ-opioid receptor binding affinity of some opiates and their metabolites. Life Sci 1991; 48: 2165–71
Sindrup SH, Brosen K, Bjerring P, et al. Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine. Clin Pharmacol Ther 1991; 49: 686–93
Shah JC, Mason WD. Plasma codeine and morphine concentrations after a single oral dose of codeine phosphate. J Clin Pharmacol 1990; 30: 764–6
Guay DRP, Awni WM, Halstenson CE, et al. Pharmacokinetics of codeine after single-and multiple-oral-dose administration to normal volunteers. J Clin Pharmacol 1987; 27: 983–7
Dahlstrom B, Tamsen A, Paalzow L, et al. Patient-controlled analgesic therapy (Pt IV): pharmacokinetics and analgesic plasma concentrations of morphine. Clin Pharmacokinet 1982; 7: 266–79
Quiding H, Oikarinen V, Sane J, et al. Analgesic efficacy after single and repeated doses of codeine and acetaminophen. J Clin Pharmacol 1984; 24: 27–34
Young RES. A two dose evaluation of propoxyphene napsylate and codeine in postoperative pain. Curr Ther Res 1978; 24: 495–502
Gruber CM. Codeine and propoxyphene in postepisiotomy pain: a two dose evaluation. JAMA 1977; 237: 2734–2735
Osborne R, Thompson P, Joel S, et al. the analgesic activity of morphine-6-glucuronide. Br J Clin Pharmacol 1992; 34: 130–8
Hand CW, Blunnie WP, Claffey LP, et al. Potential analgesic contribution from morphine-6-glucuronide in CSF. Lancet 1987; II: 1207–8
Shimomura K, Kamata O, Ueki S, et al. Analgesic effect of morphine glucuronides. Tohoku J Exp Med 1971; 105: 45–52
Davies KN, Castleden CM, McBurney A, et al. The effect of ageing on the pharmacokinetics of dihydrocodeine. Eur J Clin Pharmacol 1989; 37: 375–9
Baillie SP, Bateman DN, Coates PE, et al. Age and the pharmacokinetics of morphine. Age Ageing 1989; 18: 258–62
Bodd E, Beylich KM, Christophersen AS, et al. Oral administration of codeine in the presence of ethanol: a pharmacokinetic study in man. Pharmacol Toxicol 1987; 61: 297–300
Rogers JF, Findlay JW, Hull JH, et al. Codeine disposition in smokers and nonsmokers. Clin Pharmacol Ther 1982; 32: 218–27
Steiner E, Iselius L, Alvan G, et al. A family study of genetic and environmental factors determining polymorphic hydroxylation of debrisoquine. Clin Pharmacol Ther 1985; 38: 394–401
Dayer P, Desmeules J, Striberni R. In vitro forecasting of drugs that may interfere with codeine bioactivation. Eur J Drug Metab Pharmacokinet 1992; 17: 115–20
Romach MK, Sproule B, Kathiramalainathan K, et al. Developing medication strategies as adjuncts to treating prescription opiate dependence and comorbidity. In: Harris LS, editor. Problems of drug dependence. Proceedings of the 57th Annual Scientific Meeting of the College on Problems of Drug Dependence. Rockville: US Department of Health and Human Services, 1996: 120
Teri L, Rabins P, Whitehouse P, et al. Management of behavior disturbance in Alzheimer disease: current knowledge and future direction. Alzheimer Dis Assoc Disord 1992; 6: 77–88
Ancill RJ, Holliday SG. Treatment of depression in the elderly: a Canadian view. Prog Neuropsychopharmacol Biol Psychiatry 1990; 14: 655–61
Reisberg B, Borenstein J, Salob SP, et al. Behavioral symptoms in Alzheimer’s disease: phenomenology and treatment. J Clin Psychiatry 1987; 48 Suppl. 5: 9–15
Blazer DG, Bachar JR, Manton KG. Suicide in late life: review and commentary. J Am Geriatr Soc 1986; 34: 519–25
Eichelbaum M, Gross AS. The genetic polymorphism of debrisoquine/sparteine metabolism — clinical aspects. Pharmacol Ther 1990; 46: 377–94
Dahl ML, Johansson I, Palmertz MP, et al. Analysis of the CYP2D6 gene in relation to debrisoquine and desipramine hydroxylation in a Swedish population. Clin Pharmacol Ther 1992; 51: 12–7
Agundez JA, Ledesma MC, Ladero JM, et al. Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population. Clin Pharmacol Ther 1995; 57: 265–9
Dahl M-L, Johansson I, Bertilsson L, et al. Ultrarapid hydroxylation of debrisoquine in a Swedish population: analysis of the molecular genetic basis. J Pharmacol Exp Ther 1995; 274: 516–20
Bertilsson L, Dahl M-L, Sjöqvist F, et al. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 1993; 341: 63
Johansson I, Lundqvist E, Bertilsson L, et al. Inherited amplification of an active gene in the cytochrome P450 CYP2D-locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 1993; 90: 11825–9
Yue QY, Svensson JO, Sjöqvist F, et al. A comparison of the pharmacokinetics of codeine and its metabolites in healthy Chinese and Caucasian extensive hydroxylators of debrisoquine. Br J Clin Pharmacol 1991; 31: 643–7
Kalow W. Interethnic variation of drug metabolism. Trends Pharmacol Sci 1991; 12: 102–7
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Özdemir, V., Fourie, J., Busto, U. et al. Pharmacokinetic Changes in the Elderly. Clin-Pharmacokinet 31, 372–385 (1996). https://doi.org/10.2165/00003088-199631050-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199631050-00004