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Effects of Obesity on Pharmacokinetics

Implications for Drug Therapy

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Abstract

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.

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Notes

  1. CL CR = (140 − age) × TBW/(A) × serum creatinine where age is in years, TBW is in kg, and A = 72 for men and 85 for women.

  2. Adjusted IBW (kg) = IBW + 0.25 × (BW − IBW).

References

  1. World Health Organization. Report of a WHO Consultation on obesity: preventing and managing the global epidemic. Geneva: WHO, 1998 Jun 3–5.

    Google Scholar 

  2. Cheymol G. Clinical pharmacokinetics of drugs in obesity: an update. Clin Pharmacokinet 1993; 25: 103–14.

    Article  PubMed  CAS  Google Scholar 

  3. Blouin RA, Warren GW. Pharmacokinetic considerations in obesity. J Pharm Sci 1999; 88: 1–7.

    Article  PubMed  CAS  Google Scholar 

  4. New weight standards for men and women. Stat Bull 1959; 40: 1–3.

  5. Seidell JC. Time trends in obesity: an epidemiological perspective. Horm Metab Res 1997; 29: 155–8.

    Article  PubMed  CAS  Google Scholar 

  6. 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.

    Article  CAS  Google Scholar 

  7. 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.

    PubMed  CAS  Google Scholar 

  8. 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.

    Article  PubMed  CAS  Google Scholar 

  9. Forbes GB, Welle SL. Lean body mass in obesity. Int J Obesity 1983; 7: 99–107.

    CAS  Google Scholar 

  10. Rowland M, Tozer TN. Distribution. In: Clinical pharmacokinetics: concepts and applications. 3rd ed. Baltimore: Williams and Wilkins, 1995: 137–55.

    Google Scholar 

  11. Lesser G, Deutsch S. Measurement of adipose tissue blood flow and perfusion in man by uptake of 85Kr. J Appl Physiol 1967; 23: 621–32.

    PubMed  CAS  Google Scholar 

  12. De Divitis O, Fazio S, Pettito M, et al. Obesity and cardiac function. Circulation 1981; 64: 477–82.

    Article  Google Scholar 

  13. 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.

    Article  Google Scholar 

  14. Abernethy DR, Greenblatt DJ. Phenytoin disposition in obesity: determination of loading dose. Arch Neurol 1985; 42: 468–71.

    Article  PubMed  CAS  Google Scholar 

  15. 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.

    PubMed  CAS  Google Scholar 

  16. 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.

    Article  PubMed  CAS  Google Scholar 

  17. Diehl AM. Nonalcoholic steatohepatitis. Semin Liver Dis 1999; 19: 221–9.

    Article  PubMed  CAS  Google Scholar 

  18. 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.

    Article  PubMed  CAS  Google Scholar 

  19. 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.

    Article  PubMed  Google Scholar 

  20. Hunt CM, Watkins PB, Saenger P, et al. Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol. Clin Pharmacol Ther 1992; 51: 18–23.

    Article  PubMed  CAS  Google Scholar 

  21. Allard S, Kinzig M, Boivin G, et al. Intravenous ciprofloxacin disposition in obesity. Clin Pharmacol Ther 1993; 54: 368–73.

    Article  PubMed  CAS  Google Scholar 

  22. Reiss AR, Hass CE, Karki SD, et al. Lithium pharmacokinetics in the obese. Clin Pharmacol Ther 1994; 5: 392–8.

    Article  Google Scholar 

  23. 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.

    Google Scholar 

  24. Bauer LA, Black DJ, Lill JS. Vancomycin dosing in morbidly obese patients. Eur J Clin Pharmacol 1998; 54: 621–5.

    Article  PubMed  CAS  Google Scholar 

  25. Blouin RA, Bauer LA, Miller DD, et al. Vancomycin pharmacokinetics in normal and morbidly obese subjects. Antimicrob Agents Chemother 1982; 21: 575–80.

    Article  PubMed  CAS  Google Scholar 

  26. 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.

    Article  PubMed  CAS  Google Scholar 

  27. 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.

    Article  PubMed  CAS  Google Scholar 

  28. Caldwell JB, Kari Nilsen A. Intravenous ciprofloxacin dosing in a morbidly obese patient [letter]. Ann Pharmacother 1994; 28: 80.

    Google Scholar 

  29. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41.

    Article  Google Scholar 

  30. 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.

    Article  PubMed  CAS  Google Scholar 

  31. Gillum JG, Johnson M, Lavoie S, et al. Flucytosine dosing in an obese patient with extrameningeal cryptococal infection. Pharmacotherapy 1995; 15: 251–3.

    PubMed  CAS  Google Scholar 

  32. Glassner Cohen L, DiBiasio A, Lisco SJ, et al. Fluconazole serum concentrations and pharmacokinetics in an obese patient. Pharmacotherapy 1997; 17: 1023–6.

    Google Scholar 

  33. 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 Candida infections. Clin Infect Dis 1997; 24: 235–47.

    Article  PubMed  CAS  Google Scholar 

  34. 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.

    Article  PubMed  CAS  Google Scholar 

  35. Rodvold KA, Rushing DA, Tewksbury DA. Doxorubicin clearance in the obese. J Clin Oncol 1988; 6: 1321–7.

    PubMed  CAS  Google Scholar 

  36. 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.

    Article  PubMed  CAS  Google Scholar 

  37. 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.

    PubMed  CAS  Google Scholar 

  38. 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.

    Article  PubMed  Google Scholar 

  39. Bachur NR. Anthracycline antibiotic pharmacology and metabolism. Cancer Treat Rep 1979; 63: 817–20.

    PubMed  CAS  Google Scholar 

  40. Caraco Y, Zylber-Katz E, Berry EM, et al. Carbamazepine pharmacokinetics in obese and lean subjects. Ann Pharmacother 1995; 29: 843–7.

    PubMed  CAS  Google Scholar 

  41. Altamura AC, Moro AR, Percudani M. Clinical pharmacokinetics of fluoxetine. Clin Pharmacokinet 1994; 26: 201–14.

    Article  PubMed  CAS  Google Scholar 

  42. 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.

    Article  PubMed  CAS  Google Scholar 

  43. 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.

    Article  PubMed  CAS  Google Scholar 

  44. 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.

    Article  PubMed  CAS  Google Scholar 

  45. Dossing M. Effect of acute and chronic exercise on hepatic drug metabolism. Clin Pharmacokinet 1985; 10: 426–31.

    Article  PubMed  CAS  Google Scholar 

  46. 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.

    Article  PubMed  CAS  Google Scholar 

  47. Schwartz AE, Matteo RS, Ornstein E, et al. Pharmacokinetics of sufentanil in obese patients. Anesth Analg 1991; 73: 790–3.

    PubMed  CAS  Google Scholar 

  48. 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.

    Google Scholar 

  49. Schwartz AE, Matteo RS, Ornstein E, et al. Pharmacokinetics and pharmacodynamics of vecuronium in the obese surgical patient. Anesth Analg 1992; 74: 515–8.

    PubMed  CAS  Google Scholar 

  50. 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.

    Article  Google Scholar 

  51. Behne M, Wilke HJ, Harder S. Clinical pharmacokinetics of sevoflurane. Clin Pharmacokinet 1999; 36: 13–26.

    Article  PubMed  CAS  Google Scholar 

  52. Minto CF, Schnider TW, Shafer SL. Pharmacokinetics and pharmacodynamics of remifentanil: II. Model application. Anesthesiology 1997; 86: 24–33.

    Article  PubMed  CAS  Google Scholar 

  53. 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.

    Google Scholar 

  54. 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.

    PubMed  CAS  Google Scholar 

  55. 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.

    PubMed  Google Scholar 

  56. Garratt CJ, Hind ID, Haddock RE. Single/repeat dose kinetics of sibutramine metabolites in obese subjects [abstract]. J Clin Pharmacol 1995; 35: 928.

    Google Scholar 

  57. 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.

    Article  PubMed  CAS  Google Scholar 

  58. 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.

    Article  PubMed  CAS  Google Scholar 

  59. 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.

    CAS  Google Scholar 

  60. Kalow W, Tank BK. Use of caffeine metabolic ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther 1991; 50: 508–19.

    Article  PubMed  CAS  Google Scholar 

  61. Zahorska-Markiewicz B, Waluga M, Zielinski M, et al. Pharmacokinetics of theophylline in obesity. Int J Clin Pharmacol Ther 1996; 34: 393–5.

    PubMed  CAS  Google Scholar 

  62. 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.

    Article  PubMed  CAS  Google Scholar 

  63. 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.

    Article  PubMed  CAS  Google Scholar 

  64. 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.

    Article  Google Scholar 

  65. 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.

    PubMed  CAS  Google Scholar 

  66. 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.

    Article  PubMed  CAS  Google Scholar 

  67. Morgan DJ, Bray KM. Lean body mass as a predictor of drug dosage: implications for drug therapy. Clin Pharmacokinet 1994; 26: 292–307.

    Article  PubMed  CAS  Google Scholar 

  68. 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.

    Google Scholar 

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Acknowledgements

I thank Mr Owen Parkes for editing the English text.

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Cheymol, G. Effects of Obesity on Pharmacokinetics. Clin Pharmacokinet 39, 215–231 (2000). https://doi.org/10.2165/00003088-200039030-00004

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