Effects of Obesity on Pharmacokinetics
Implications for Drug Therapy
Review Article Special Populations
First Online: 30 September 2012 DOI:
10.2165/00003088-200039030-00004 Cite this article as: Cheymol, G. Clin Pharmacokinet (2000) 39: 215. doi:10.2165/00003088-200039030-00004
Obesity is a worldwide problem, with major health, social and economic implications. The adaptation of drug dosages to obese patients is a subject of concern, particularly for drugs with a narrow therapeutic index. The main factors that affect the tissue distribution of drugs are body composition, regional blood flow and the affinity of the drug for plasma proteins and/or tissue components.
Obese people have larger absolute lean body masses as well as fat masses than non-obese individuals of the same age, gender and height. However, the percentage of fat per kg of total bodyweight (TBW) is markedly increased, whereas that of lean tissue is reduced. Cardiac performance and adipose tissue blood flow may be altered in obesity. There is uncertainty about the binding of drugs to plasma proteins in obese patients. Some data suggest that the activities of hepatic cytochrome P450 isoforms are altered, but no clear overview of drug hepatic metabolism in obesity is currently available. Pharmacokinetic studies provide differing data on renal function in obese patients.
This review analyses recent publications on several classes of drugs: antibacterials, anticancer drugs, psychotropic drugs, anticonvulsants, general anaesthetics, opioid analgesics, neuromuscular blockers, β-blockers and drugs commonly used in the management of obesity. Pharmacokinetic studies in obesity show that the behaviour of molecules with weak or moderate lipophilicity (e.g. lithium and vecuronium) is generally rather predictable, as these drugs are distributed mainly in lean tissues. The dosage of these drugs should be based on the ideal bodyweight (IBW). However, some of these drugs (e.g. antibacterials and some anticancer drugs) are partly distributed in adipose tissues, and their dosage is based on IBW plus a percentage of the patient’s excess bodyweight.
There is no systematic relationship between the degree of lipophilicity of markedly lipophilic drugs (e.g. remifentanil and some β-blockers) and their distribution in obese individuals. The distribution of a drug between fat and lean tissues may influence its pharmacokinetics in obese patients. Thus, the loading dose should be adjusted to the TBW or IBW, according to data from studies carried out in obese individuals. Adjustment of the maintenance dosage depends on the observed modifications in clearance.
Our present knowledge of the influence of obesity on drug pharmacokinetics is limited. Drugs with a small therapeutic index should be used prudently and the dosage adjusted with the help of drug plasma concentrations.
World Health Organization. Report of a WHO Consultation on obesity: preventing and managing the global epidemic. Geneva: WHO, 1998 Jun 3–5.
Cheymol G. Clinical pharmacokinetics of drugs in obesity: an update. Clin Pharmacokinet 1993; 25: 103–14.
Blouin RA, Warren GW. Pharmacokinetic considerations in obesity. J Pharm Sci 1999; 88: 1–7.
New weight standards for men and women. Stat Bull 1959; 40: 1–3.
Seidell JC. Time trends in obesity: an epidemiological perspective. Horm Metab Res 1997; 29: 155–8.
Maillard G, Charles MA, Thibult N, et al. Trends in the prevalence of obesity in the French adult population between 1980 and 1991. Int J Obes 1999; 23: 389–94.
Lehingue Y, Picot MC, Millot I, et al. Increase in the prevalence of obesity among children aged 4–5 years in a French district between 1988 and 1993. Rev Epidemiol Sante Publique 1996; 44: 37–46.
Galuska DA, Serdula M, Pamuk E, et al. Trends in overweight among US adults from 1987 to 1993: a multistate telephone survey. Am J Public Health 1996; 86: 1729–35.
Forbes GB, Welle SL. Lean body mass in obesity. Int J Obesity 1983; 7: 99–107.
Rowland M, Tozer TN. Distribution. In: Clinical pharmacokinetics: concepts and applications. 3rd ed. Baltimore: Williams and Wilkins, 1995: 137–55.
Lesser G, Deutsch S. Measurement of adipose tissue blood flow and perfusion in man by uptake of
Kr. J Appl Physiol 1967; 23: 621–32.
De Divitis O, Fazio S, Pettito M, et al. Obesity and cardiac function. Circulation 1981; 64: 477–82.
Benedeck IH, Blouin A, McNamara PJ. Serum protein binding and the role of increased alpha 1-acid glycoprotein in moderately obese male subjects. Br J Clin Pharmacol 1984; 18: 941–6.
Abernethy DR, Greenblatt DJ. Phenytoin disposition in obesity: determination of loading dose. Arch Neurol 1985; 42: 468–71.
Cheymol G, Poirier JM, Barré J, et al. Comparative pharmacokinetics of intravenous propranolol in obese and normal volunteers. J Clin Pharmacol 1987; 27: 874–9.
Derry CL, Kroboth PD, Pittenger AL, et al. Pharmacokinetics and pharmacodynamics of triazolam after two intermittent doses in obese and normal-weight men. J Clin Psychopharmacol 1995; 15: 197–205.
Diehl AM. Nonalcoholic steatohepatitis. Semin Liver Dis 1999; 19: 221–9.
Caraco Y, Zylber-Katz E, Berry EM, et al. Antipyrine disposition in obesity: evidence for negligible effect of obesity on hepatic oxidative metabolism. Eur J Clin Pharmacol 1995; 47: 525–30.
O’shea D, Davis SN, Kim RB, et al. Effect of fasting and obesity in humans on the 6-hydroxylation of chlorzoxazone: a putative probe of CYP2E1 activity. Clin Pharmacol Ther 1994; 56: 359–67.
Hunt CM, Watkins PB, Saenger P, et al. Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol. Clin Pharmacol Ther 1992; 51: 18–23.
Allard S, Kinzig M, Boivin G, et al. Intravenous ciprofloxacin disposition in obesity. Clin Pharmacol Ther 1993; 54: 368–73.
Reiss AR, Hass CE, Karki SD, et al. Lithium pharmacokinetics in the obese. Clin Pharmacol Ther 1994; 5: 392–8.
Leader WG, Tsubaki T, Chandler MHH. Creatinine-clearance estimates for predicting gentamicin pharmacokinetic values in obese patients. Am J Hosp Pharm 1994; 51: 2155–30.
Bauer LA, Black DJ, Lill JS. Vancomycin dosing in morbidly obese patients. Eur J Clin Pharmacol 1998; 54: 621–5.
Blouin RA, Bauer LA, Miller DD, et al. Vancomycin pharmacokinetics in normal and morbidly obese subjects. Antimicrob Agents Chemother 1982; 21: 575–80.
Vance-Bryan K, Guay DRP, Gilliland SS, et al. Effect of obesity on vancomycin pharmacokinetic parameters as determined by using a Bayesian forecasting technique. Antimicrob Agents Chemother 1993; 37: 436–40.
Penzak SR, Gubbins PO, Rodvold KA, et al. Therapeutic drug monitoring of vancomycin in a morbidly obese patient. Ther Drug Monit 1998; 20: 261–5.
Caldwell JB, Kari Nilsen A. Intravenous ciprofloxacin dosing in a morbidly obese patient [letter]. Ann Pharmacother 1994; 28: 80.
Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41.
Salazar DE, Corcoran GB. Predicting creatinine clearance and renal drug clearance in obese patients from estimated fat-free body mass. Am J Med 1988; 84: 1053–60.
Gillum JG, Johnson M, Lavoie S, et al. Flucytosine dosing in an obese patient with extrameningeal cryptococal infection. Pharmacotherapy 1995; 15: 251–3.
Glassner Cohen L, DiBiasio A, Lisco SJ, et al. Fluconazole serum concentrations and pharmacokinetics in an obese patient. Pharmacotherapy 1997; 17: 1023–6.
Rex JH, Pfaller MA, Galgiani JN, et al. Development of interpretative breakpoints for antifungal susceptibility testing: conceptual framework and analysis of the in vitro — in vivo correlation data for fluconazole, itraconazole, and
infections. Clin Infect Dis 1997; 24: 235–47.
Lind MJ, Margison JM, Cerny T, et al. Prolongation of ifosfamide elimination half-life in obese patients due to altered drug distribution. Cancer Chemother Pharmacol 1989; 25: 139–42.
Rodvold KA, Rushing DA, Tewksbury DA. Doxorubicin clearance in the obese. J Clin Oncol 1988; 6: 1321–7.
Powis G, Reece P, Ahmann DL, et al. Effect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients. Cancer Chemother Pharmacol 1987; 20: 219–22.
Gibbs JP, Gooley T, Corneau B, et al. The impact of obesity and disease on busulfan oral clearance in adults. Blood 1999; 93: 4436–40.
Bénézet S, Guimbaud R, Chatelut E, et al. How to predict carboplatin clearance from standard morphological and biological characteristics in obese patients. Ann Oncol 1997; 8: 607–9.
Bachur NR. Anthracycline antibiotic pharmacology and metabolism. Cancer Treat Rep 1979; 63: 817–20.
Caraco Y, Zylber-Katz E, Berry EM, et al. Carbamazepine pharmacokinetics in obese and lean subjects. Ann Pharmacother 1995; 29: 843–7.
Altamura AC, Moro AR, Percudani M. Clinical pharmacokinetics of fluoxetine. Clin Pharmacokinet 1994; 26: 201–14.
Olsen KM, Marx MA, Monoghan MS, et al. Phenytoin and plasmapheresis: importance of sampling times and impact of obesity. Ther Drug Monit 1994; 16: 624–8.
Kuranari M, Chiba S, Ashikari Y, et al. Clearance of phenytoin and valproic acid is affected by a small body weight reduction in an epileptic obese patient: a case study. J Clin Pharm Ther 1996; 21: 83–7.
Caraco Y, Zylber-Karz E, Berry EM, et al. Significant weight reduction in obese subjects enhances carbamazepine elimination. Clin Pharmacol Ther 1992; 51: 501–6.
Dossing M. Effect of acute and chronic exercise on hepatic drug metabolism. Clin Pharmacokinet 1985; 10: 426–31.
Servin F, Farinoti R, Haberer JP, et al. Propofol infusion for maintenance of anesthesia in morbidly obese patients receiving nitrous oxide: a clinical and pharmacokinetic study. Anesthesiology 1993; 78: 657–65.
Schwartz AE, Matteo RS, Ornstein E, et al. Pharmacokinetics of sufentanil in obese patients. Anesth Analg 1991; 73: 790–3.
Evan TD, Gupta SK, Sperry RJ, et al. The pharmacokinetics of remifentanil in obese versus lean elective surgery patients. Anesth Analg 1996; 82 Suppl.: S100.
Schwartz AE, Matteo RS, Ornstein E, et al. Pharmacokinetics and pharmacodynamics of vecuronium in the obese surgical patient. Anesth Analg 1992; 74: 515–8.
Mann R, Blibner M, Probst R, et al. Pharmacokinetics of rocuronium in obese and asthenic patients: reduced clearance in the obese [abstract]. Anesthesiology 1997; 87: A85.
Behne M, Wilke HJ, Harder S. Clinical pharmacokinetics of sevoflurane. Clin Pharmacokinet 1999; 36: 13–26.
Minto CF, Schnider TW, Shafer SL. Pharmacokinetics and pharmacodynamics of remifentanil: II. Model application. Anesthesiology 1997; 86: 24–33.
Pühringer FK, Khuenl-Brady KS, Mitterschiffhaler G. Rocuronium bromide: time-course of action in underweight, normal weight, overweight and obese patients. Eur J Anaesth 1995; 12 Suppl. 11: 107–10.
Cheymol G, Weissenburger J, Poirier JM, et al. The pharmacokinetics of dexfenfluramine in obese and non-obese subjects. Br J Clin Pharmacol 1995; 39: 684–7.
Campbell BD, Ings RMJ, Richards RP, et al. Factors which may affect the reduction of hunger and body weight following d-fenfluramine administration. Clin Neuropharmacol 1988; 11 Suppl. 1: S160–72.
Garratt CJ, Hind ID, Haddock RE. Single/repeat dose kinetics of sibutramine metabolites in obese subjects [abstract]. J Clin Pharmacol 1995; 35: 928.
Jaber LA, Ducharme MP, Halapy H. The effects of obesity on the pharmacokinetics and pharmacodynamics of glipizide in patients with non-insulin-dependant diabetes mellitus. Ther Drug Monit 1996; 18: 6–13.
Jaber LA, Antal EJ, Slaughter RL, et al. The pharmacokinetics and pharmacodynamics of 12 weeks of glyburide therapy in obese diabetics. Eur J Clin Pharmacol 1993; 45: 459–63.
Caraco Y, Zylber-Katz E, Berry EM, et al. Caffeine pharmacokinetics in obesity and following significant weight reduction. Int J Obes 1995; 19: 234–9.
Kalow W, Tank BK. Use of caffeine metabolic ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther 1991; 50: 508–19.
Zahorska-Markiewicz B, Waluga M, Zielinski M, et al. Pharmacokinetics of theophylline in obesity. Int J Clin Pharmacol Ther 1996; 34: 393–5.
Poirier JM, Le Jeune C, Cheymol G, et al. Comparison of propranolol and sotalol pharmacokinetics in obese subjects. J Pharm Pharmacol 1990; 42: 344–8.
Cheymol G, Poirier JM, Carrupt PA, et al. Pharmacokinetics of ß-adrenoceptor blockers in obese and normal volunteers. Br J Clin Pharmacol 1997; 43: 563–70.
Le Jeune C, Poirier JM, Cheymol G, et al. Pharmacokinetics of i.v. bisoprolol in obese and non-obese volunteers. Eur J Clin Pharmacol 1991; 41: 171–4.
Prather RD, Tu TG, Rolf CN, et al. Nicotine pharmacokinetics of Nicoderm® (nicotine transdermal system) in women and obese men compared with normal-sized men. J Clin Pharmacol 1993; 33: 644–9.
Lam NP, Pitrak D, Speralakis R, et al. Effect of obesity on pharmacokinetics and biologic effect of interferon-α in hepatitis C. Dig Dis Sci 1997; 42: 178–85.
Morgan DJ, Bray KM. Lean body mass as a predictor of drug dosage: implications for drug therapy. Clin Pharmacokinet 1994; 26: 292–307.
Bickel MH. Factors affecting the storage of drugs and other xenobiotics in adipose tissue. In: Testa B, Meyer UA, editors. Advances in drug research. Vol. 25. London: Academic Press, 1994: 55–86.
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