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Journal of Pharmaceutical Investigation

, Volume 43, Issue 3, pp 161–169 | Cite as

Obesity-related physiological changes and their pharmacokinetic consequences

  • Sung-Joon Cho
  • In-Soo Yoon
  • Dae-Duk KimEmail author
Review

Abstract

The prevalence of obesity has soared in recent decades, and now is considered as a worldwide problem, with significant health and medical implications. Obesity is often linked to several co-morbidities including diabetes, cardiovascular diseases, and cancers, and a number of drugs are available for the treatment of these diseases. Moreover, obesity can affect various physiological factors including plasma proteins, drug metabolizing enzymes, drug transporters, and blood flow, thereby altering drug absorption, distribution, metabolism, and excretion (ADME). Therefore, information regarding obesity-related physiological changes and their pharmacokinetic consequences is crucial for understanding pharmacokinetics and optimizing drug therapy in obese population. Herein, this article reviews the effects of obesity on physiological factors determining drug ADME and their pharmacokinetic consequences. In addition, a brief summary on animal models of obesity is presented.

Keywords

Obesity Pharmacokinetics Animal models 

Abbreviations

CL

Total body clearance

CLH

Hepatic clearance

CLR

Renal clearance

Vd

Volume of distribution

Tmax

Time to reach a peak plasma concentration

F

Extent of absolute oral bioavailability

fu

Free fraction of a drug in plasma

EH

Hepatic extraction ratio

NASH

Non-alcoholic steatohepatitis

NAFLH

Non-alcoholic fatty liver hepatitis

CPR

NADPH-cytochrome P450 reductase

Notes

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No. 2009-0083533 and 2011-0016040).

References

  1. Abernethy DR, Greenblatt DJ, Divoll M, Harmatz JS, Shader RI (1981a) Alterations in drug distribution and clearance due to obesity. J Pharmacol Exp Ther 217(3):681–685PubMedGoogle Scholar
  2. Abernethy DR, Greenblatt DJ, Smith TW (1981b) Digoxin disposition in obesity: clinical pharmacokinetic investigation. Am Heart J 102(4):740–744PubMedCrossRefGoogle Scholar
  3. Abernethy DR, Divoll M, Greenblatt DJ, Ameer B (1982a) Obesity, sex, and acetaminophen disposition. Clin Pharmacol Ther 31(6):783–790PubMedCrossRefGoogle Scholar
  4. Abernethy DR, Greenblatt DJ, Divoll M, Shader RI (1982b) Prolongation of drug half-life due to obesity: studies of desmethyldiazepam (clorazepate). J Pharm Sci 71(8):942–944PubMedCrossRefGoogle Scholar
  5. Adams J, Murphy P (2000) Obesity in anaesthesia and intensive care. Br J Anaesth 85(1):91–108PubMedCrossRefGoogle Scholar
  6. Al-Jahdari WS, Yamamoto K, Hiraoka H, Nakamura K, Goto F, Horiuchi R (2006) Prediction of total propofol clearance based on enzyme activities in microsomes from human kidney and liver. Eur J Clin Pharmacol 62(7):527–533PubMedCrossRefGoogle Scholar
  7. Allard S, Kinzig M, Boivin G, Sörgel F, Lebel M (1993) Intravenous ciprofloxacin disposition in obesity. Clin Pharmacol Ther 54(4):368–373PubMedCrossRefGoogle Scholar
  8. Banks WA, Coon AB, Robinson SM, Moinuddin A, Shultz JM, Nakaoke R, Morley JE (2004) Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes 53(5):1253–1260PubMedCrossRefGoogle Scholar
  9. Barras MA, Duffull SB, Atherton JJ, Green B (2009) Modelling the occurrence and severity of enoxaparin-induced bleeding and bruising events. Br J Clin Pharmacol 68(5):700–711PubMedCrossRefGoogle Scholar
  10. Barrett J, Gibiansky E, Hull R, Planes A, Pentikis H, Hainer J, Hua T, Gastonguay M (2001) Population pharmacodynamics in patients receiving tinzaparin for the prevention and treatment of deep vein thrombosis. Int J Clin Pharmacol Ther 39(10):431PubMedGoogle Scholar
  11. Bauer L, Black D, Lill J (1998) Vancomycin dosing in morbidly obese patients. Eur J Clin Pharmacol 54(8):621–625PubMedCrossRefGoogle Scholar
  12. Benedek I, Blouin R, McNamara P (2012a) Serum protein binding and the role of increased alpha 1-acid glycoprotein in moderately obese male subjects. Br J Clin Pharmacol 18(6):941–946CrossRefGoogle Scholar
  13. Benedek I, Griffen W, Bell R, Blouin R, McNamara P (2012b) Serum alpha 1-acid glycoprotein and the binding of drugs in obesity. Br J Clin Pharmacol 16(6):751–754CrossRefGoogle Scholar
  14. Blouin RA, Warren GW (1999) Pharmacokinetic considerations in obesity. J Pharm Sci 88(1):1–7PubMedCrossRefGoogle Scholar
  15. Bowman S, Hudson S, Simpson G, Munro J, Clements J (2012) A comparison of the pharmacokinetics of propranolol in obese and normal volunteers. Br J Clin Pharmacol 21(5):529–532CrossRefGoogle Scholar
  16. Brill MJE, Diepstraten J, van Rongen A, van Kralingen S, van den Anker JN, Knibbe CAJ (2012) Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet 51(5):277PubMedCrossRefGoogle Scholar
  17. Bryson SM (1983) Clinical Pharmacokinetics: concepts and applications. J Clin Pharmacol Ther 8(1):87–88CrossRefGoogle Scholar
  18. Casati A, Putzu M (2005) Anesthesia in the obese patient: pharmacokinetic considerations. J Clin Anesth 17(2):134–145PubMedCrossRefGoogle Scholar
  19. Chagnac A, Herman M, Zingerman B, Erman A, Rozen-Zvi B, Hirsh J, Gafter U (2008) Obesity-induced glomerular hyperfiltration: its involvement in the pathogenesis of tubular sodium reabsorption. Nephrol Dial Transplant 23(12):3946–3952PubMedCrossRefGoogle Scholar
  20. Cheymol G, Poirier JM, Carrupt PA, Testa B, Weissenburger J, Levron JC, Snoeck E (1997) Pharmacokinetics of β-adrenoceptor blockers in obese and normal volunteers. Br J Clin Pharmacol 43(6):563–570PubMedCrossRefGoogle Scholar
  21. Chiney MS, Schwarzenberg SJ, Johnson LAA (2011) Altered xanthine oxidase and N-acetyltransferase activity in obese children. Br J Clin Pharmacol 72(1):109–115PubMedCrossRefGoogle Scholar
  22. Clegg DJ, Gotoh K, Kemp C, Wortman MD, Benoit SC, Brown LM, D’Alessio D, Tso P, Seeley RJ, Woods SC (2011) Consumption of a high-fat diet induces central insulin resistance independent of adiposity. Physiol Behav 103(1):10–16PubMedCrossRefGoogle Scholar
  23. Cortinez L, Anderson B, Penna A, Olivares L, Muñoz H, Holford N, Struys M, Sepulveda P (2010) Influence of obesity on propofol pharmacokinetics: derivation of a pharmacokinetic model. Br J Anaesth 105(4):448–456PubMedCrossRefGoogle Scholar
  24. Daley-Yates PT, Mcbrien DCH (1982) The mechanism of renal clearance of cisplatin (< i > cis </i > -dichlorodiammine platinum II) and its modification by furosemide and probenecid. Biochem Pharmacol 31(13):2243–2246PubMedCrossRefGoogle Scholar
  25. Drusano G (1987) An overview of the pharmacology of intravenously administered ciprofloxacin. Am J Med 82(4A):339PubMedGoogle Scholar
  26. Edelman AB, Cherala G, Stanczyk FZ (2010) Metabolism and pharmacokinetics of contraceptive steroids in obese women: a review. Contraception 82(4):314PubMedCrossRefGoogle Scholar
  27. Ekhart C, Rodenhuis S, Schellens JHM, Beijnen JH, Huitema ADR (2009) Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter? Cancer Chemother Pharmacol 64(1):115–122PubMedCrossRefGoogle Scholar
  28. Emery MG, Fisher JM, Chien JY, Kharasch ED, Dellinger EP, Kowdley KV, Thummel KE (2003) CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease. Hepatology 38(2):428–435PubMedCrossRefGoogle Scholar
  29. Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286(5439):487–491PubMedCrossRefGoogle Scholar
  30. Farrell GC, Teoh N, McCuskey R (2008) Hepatic microcirculation in fatty liver disease. Anat Rec Adv Integr Anat Evol Biol 291(6):684–692CrossRefGoogle Scholar
  31. Flechner SM, Kolbeinsson ME, Tam J, Lum B (1989) The impact of body weight on cyclosporine pharmacokinetics in renal transplant recipients. Transplantation 47(5):806–810PubMedCrossRefGoogle Scholar
  32. Geier A, Dietrich CG, Grote T, Beuers U, Prüfer T, Fraunberger P, Matern S, Gartung C, Gerbes AL, Bilzer M (2005) Characterization of organic anion transporter regulation, glutathione metabolism and bile formation in the obese Zucker rat. J Hepatol 43(6):1021–1030PubMedCrossRefGoogle Scholar
  33. Gibbs JP, Gooley T, Corneau B, Murray G, Stewart P, Appelbaum FR, Slattery JT (1999) The impact of obesity and disease on busulfan oral clearance in adults. Blood 93(12):4436–4440PubMedGoogle Scholar
  34. Gomez-Lechon MJ, Jover R, Donato MT (2009) Cytochrome P450 and steatosis. Curr Drug Metab 10(7):692PubMedCrossRefGoogle Scholar
  35. Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI (1984) Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology 61(1):27PubMedGoogle Scholar
  36. Guengerich FP (2007) Cytochrome P450 and chemical toxicology. Chem Res Toxicol 21(1):70–83PubMedCrossRefGoogle Scholar
  37. Hardwick RN, Fisher CD, Canet MJ, Scheffer GL, Cherrington NJ (2011) Variations in ATP-binding cassette transporter regulation during the progression of human nonalcoholic fatty liver disease. Drug Metab Dispos 39(12):2395–2402PubMedCrossRefGoogle Scholar
  38. Hariri N, Thibault L (2010) High-fat diet-induced obesity in animal models. Nutr Res Rev 23(2):270PubMedCrossRefGoogle Scholar
  39. Harland SJ, Newell DR, Siddik ZH, Chadwick R, Calvert AH, Harrap KR (1984) Pharmacokinetics of cis-diammine-1, 1-cyclobutane dicarboxylate platinum (II) in patients with normal and impaired renal function. Cancer Res 44(4):1693–1697PubMedGoogle Scholar
  40. Jain R, Chung S, Jain L, Khurana M, Lau S, Lee J, Vaidyanathan J, Zadezensky I, Choe S, Sahajwalla C (2011) Implications of obesity for drug therapy: limitations and challenges. Clin Pharmacol Ther 90(1):77–89PubMedCrossRefGoogle Scholar
  41. Jump DB, Botolin D, Wang Y, Xu J, Christian B, Demeure O (2005) Fatty acid regulation of hepatic gene transcription. J Nutr 135(11):2503–2506PubMedGoogle Scholar
  42. Jung D, Mayersohn M, Perrier D, Calkins J, Saunders R (1982) Thiopental disposition in lean and obese patients undergoing surgery. Anesthesiology 56(4):269PubMedCrossRefGoogle Scholar
  43. Kasiske BL, Crosson JT (1986) Renal disease in patients with massive obesity. Arch Intern Med 146(6):1105PubMedCrossRefGoogle Scholar
  44. Kelly T, Yang W, Chen C, Reynolds K, He J (2008) Global burden of obesity in 2005 and projections to 2030. Int J Obes 32(9):1431–1437CrossRefGoogle Scholar
  45. Kiang TKL, Ensom MHH, Chang TKH (2005) UDP-glucuronosyltransferases and clinical drug–drug interactions. Pharmacol Ther 106(1):97–132PubMedCrossRefGoogle Scholar
  46. Lam JL, Jiang Y, Zhang T, Zhang EY, Smith BJ (2010) Expression and functional analysis of hepatic cytochromes P450, nuclear receptors, and membrane transporters in 10-and 25-week-old db/db mice. Drug Metab Dispos 38(12):2252–2258PubMedCrossRefGoogle Scholar
  47. Leclercq I, Horsmans Y, Desager JP, Delzenne N, Geubel AP (1998) Reduction in hepatic cytochrome P-450 is correlated to the degree of liver fat content in animal models of steatosis in the absence of inflammation. J Hepatol 28(3):410–416PubMedCrossRefGoogle Scholar
  48. Lesser GT, Deutsch S (1967) Measurement of adipose tissue blood flow and perfusion in man by uptake of 85Kr. J Appl Physiol 23(5):621–630PubMedGoogle Scholar
  49. Levin BE, Dunn-Meynell AA (2000) Defense of body weight against chronic caloric restriction in obesity-prone and-resistant rats. Am J Physiol Regul Integr Comp Physiol 278(1):R231–R237PubMedGoogle Scholar
  50. Leykin Y, Miotto L, Pellis T (2011) Pharmacokinetic considerations in the obese. Best Pract Res Clin Anaesthesiol 25(1):27–36PubMedCrossRefGoogle Scholar
  51. Lickteig AJ, Fisher CD, Augustine LM, Aleksunes LM, Besselsen DG, Slitt AL, Manautou JE, Cherrington NJ (2007) Efflux transporter expression and acetaminophen metabolite excretion are altered in rodent models of nonalcoholic fatty liver disease. Drug Metab Dispos 35(10):1970–1978PubMedCrossRefGoogle Scholar
  52. May DG (1994) Genetic differences in drug disposition. J Clin Pharmacol 34(9):881–897PubMedCrossRefGoogle Scholar
  53. More VR, Slitt AL (2011) Alteration of hepatic but not renal transporter expression in diet-induced obese mice. Drug Metab Dispos 39(6):992–999PubMedCrossRefGoogle Scholar
  54. Morrish GA, Pai MP, Green B (2011) The effects of obesity on drug pharmacokinetics in humans. Expert Opin Drug Metab Toxicol 7(6):697–706PubMedCrossRefGoogle Scholar
  55. O’Rahilly S (2009) Human genetics illuminates the paths to metabolic disease. Nature 462(7271):307–314PubMedCrossRefGoogle Scholar
  56. Pai MP (2010) Estimating the glomerular filtration rate in obese adult patients for drug dosing. Adv Chronic Kidney Dis 17(5):e53–e62PubMedCrossRefGoogle Scholar
  57. Pai MP, Norenberg JP, Anderson T, Goade DW, Rodvold KA, Telepak RA, Mercier RC (2007) Influence of morbid obesity on the single-dose pharmacokinetics of daptomycin. Antimicrob Agents Chemother 51(8):2741–2747PubMedCrossRefGoogle Scholar
  58. Reiss RA, Haas CE, Karki SD, Gumbiner B, Welle SL, Carson SW (1994) Lithium pharmacokinetics in the obese. Clin Pharmacol Ther 55(4):392–398PubMedCrossRefGoogle Scholar
  59. Rinella ME, Elias MS, Smolak RR, Fu T, Borensztajn J, Green RM (2008) Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J Lipid Res 49(5):1068–1076PubMedCrossRefGoogle Scholar
  60. Sanderink GJ, Le Liboux A, Jariwala N, Harding N, Ozoux ML, Shukla U, Montay G, Boutouyrie B, Miro A (2002) The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers&ast. Clin Pharmacol Ther 72(3):308–318PubMedCrossRefGoogle Scholar
  61. Schmitt A, Gladieff L, Lansiaux A, Bobin-Dubigeon C, Etienne-Grimaldi MC, Boisdron-Celle M, Serre-Debauvais F, Pinguet F, Floquet A, Billaud E (2009) A universal formula based on cystatin C to perform individual dosing of carboplatin in normal weight, underweight, and obese patients. Clin Cancer Res 15(10):3633–3639PubMedCrossRefGoogle Scholar
  62. Sparreboom A, Wolff AC, Mathijssen RHJ, Chatelut E, Rowinsky EK, Verweij J, Baker SD (2007) Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese. J Clin Oncol 25(30):4707–4713PubMedCrossRefGoogle Scholar
  63. Speakman J, Hambly C, Mitchell S, Krol E (2007) Animal models of obesity. Obes Rev 8(s1):55–61PubMedCrossRefGoogle Scholar
  64. Su GM, Sefton RM, Murray M (1999) Down-regulation of rat hepatic microsomal cytochromes P-450 in microvesicular steatosis induced by orotic acid. J Pharmacol Exp Ther 291(3):953–959PubMedGoogle Scholar
  65. van Kralingen S, Diepstraten J, Peeters MYM, Deneer VHM, van Ramshorst B, Wiezer RJ, van Dongen E, Danhof M, Knibbe CAJ (2011) Population pharmacokinetics and pharmacodynamics of propofol in morbidly obese patients. Clin Pharmacokinet 50(11):739–750PubMedCrossRefGoogle Scholar
  66. Wisén O, Hellström P (1995) Gastrointestinal motility in obesity. J Intern Med 237(4):411–418PubMedCrossRefGoogle Scholar
  67. Wójcicki J, Jaroszynska M, Droździk M, Pawlik A, Gawrońska-Szklarz B, Sterna R (2003) Comparative pharmacokinetics and pharmacodynamics of propranolol and atenolol in normolipaemic and hyperlipidaemic obese subjects. Biopharm Drug Dispos 24(5):211–218PubMedCrossRefGoogle Scholar
  68. Wright R, Krinsky S, Fleeman C, Trujillo J, Teague E (1983) Gastric emptying and obesity. Gastroenterology 84(4):747PubMedGoogle Scholar
  69. Yee J, Duffull S (2000) The effect of body weight on dalteparin pharmacokinetics. A preliminary study. Eur J Clin Pharmacol 56(4):293–297PubMedCrossRefGoogle Scholar
  70. Yee GC, Lennon TP, Gmur DJ, Cheney CL, Oeser D, Deeg HJ (1988) Effect of obesity on cyclosporine disposition. Transplantation 45(3):649–650PubMedCrossRefGoogle Scholar
  71. Zahorska-Markiewicz B, Jonderko K, Lelek A, Skrzypek D (1986) Gastric emptying in obesity. Hum Nutr Clin Nutr 40(4):309PubMedGoogle Scholar

Copyright information

© The Korean Society of Pharmaceutical Sciences and Technology 2013

Authors and Affiliations

  1. 1.College of Pharmacy and Research Institute of Pharmlaceutical Sciences, Seoul National UniversitySeoulRepublic of Korea
  2. 2.College of Pharmacy and Natural Medicine Research Institute, Mokpo National UniversityJeonnamRepublic of Korea

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