Skip to main content
SpringerLink
Log in

Obesity-related physiological changes and their pharmacokinetic consequences

  • Review
  • Published:
Journal of Pharmaceutical Investigation Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

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

References

  • 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):681–685

    PubMed  CAS  Google Scholar 

  • Abernethy DR, Greenblatt DJ, Smith TW (1981b) Digoxin disposition in obesity: clinical pharmacokinetic investigation. Am Heart J 102(4):740–744

    Article  PubMed  CAS  Google Scholar 

  • Abernethy DR, Divoll M, Greenblatt DJ, Ameer B (1982a) Obesity, sex, and acetaminophen disposition. Clin Pharmacol Ther 31(6):783–790

    Article  PubMed  CAS  Google Scholar 

  • 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):942–944

    Article  PubMed  CAS  Google Scholar 

  • Adams J, Murphy P (2000) Obesity in anaesthesia and intensive care. Br J Anaesth 85(1):91–108

    Article  PubMed  CAS  Google Scholar 

  • 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):527–533

    Article  PubMed  CAS  Google Scholar 

  • Allard S, Kinzig M, Boivin G, Sörgel F, Lebel M (1993) Intravenous ciprofloxacin disposition in obesity. Clin Pharmacol Ther 54(4):368–373

    Article  PubMed  CAS  Google Scholar 

  • 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):1253–1260

    Article  PubMed  CAS  Google Scholar 

  • 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):700–711

    Article  PubMed  CAS  Google Scholar 

  • 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):431

    PubMed  CAS  Google Scholar 

  • Bauer L, Black D, Lill J (1998) Vancomycin dosing in morbidly obese patients. Eur J Clin Pharmacol 54(8):621–625

    Article  PubMed  CAS  Google Scholar 

  • 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):941–946

    Article  Google Scholar 

  • 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):751–754

    Article  Google Scholar 

  • Blouin RA, Warren GW (1999) Pharmacokinetic considerations in obesity. J Pharm Sci 88(1):1–7

    Article  PubMed  CAS  Google Scholar 

  • 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):529–532

    Article  Google Scholar 

  • 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):277

    Article  PubMed  CAS  Google Scholar 

  • Bryson SM (1983) Clinical Pharmacokinetics: concepts and applications. J Clin Pharmacol Ther 8(1):87–88

    Article  Google Scholar 

  • Casati A, Putzu M (2005) Anesthesia in the obese patient: pharmacokinetic considerations. J Clin Anesth 17(2):134–145

    Article  PubMed  CAS  Google Scholar 

  • 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):3946–3952

    Article  PubMed  CAS  Google Scholar 

  • 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):563–570

    Article  PubMed  CAS  Google Scholar 

  • Chiney MS, Schwarzenberg SJ, Johnson LAA (2011) Altered xanthine oxidase and N-acetyltransferase activity in obese children. Br J Clin Pharmacol 72(1):109–115

    Article  PubMed  CAS  Google Scholar 

  • 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):10–16

    Article  PubMed  CAS  Google Scholar 

  • 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):448–456

    Article  PubMed  CAS  Google Scholar 

  • 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):2243–2246

    Article  PubMed  CAS  Google Scholar 

  • Drusano G (1987) An overview of the pharmacology of intravenously administered ciprofloxacin. Am J Med 82(4A):339

    PubMed  CAS  Google Scholar 

  • Edelman AB, Cherala G, Stanczyk FZ (2010) Metabolism and pharmacokinetics of contraceptive steroids in obese women: a review. Contraception 82(4):314

    Article  PubMed  CAS  Google Scholar 

  • 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):115–122

    Article  PubMed  CAS  Google Scholar 

  • 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):428–435

    Article  PubMed  CAS  Google Scholar 

  • Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286(5439):487–491

    Article  PubMed  CAS  Google Scholar 

  • Farrell GC, Teoh N, McCuskey R (2008) Hepatic microcirculation in fatty liver disease. Anat Rec Adv Integr Anat Evol Biol 291(6):684–692

    Article  Google Scholar 

  • Flechner SM, Kolbeinsson ME, Tam J, Lum B (1989) The impact of body weight on cyclosporine pharmacokinetics in renal transplant recipients. Transplantation 47(5):806–810

    Article  PubMed  CAS  Google Scholar 

  • 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):1021–1030

    Article  PubMed  CAS  Google Scholar 

  • 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):4436–4440

    PubMed  CAS  Google Scholar 

  • Gomez-Lechon MJ, Jover R, Donato MT (2009) Cytochrome P450 and steatosis. Curr Drug Metab 10(7):692

    Article  PubMed  CAS  Google Scholar 

  • 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):27

    PubMed  CAS  Google Scholar 

  • Guengerich FP (2007) Cytochrome P450 and chemical toxicology. Chem Res Toxicol 21(1):70–83

    Article  PubMed  Google Scholar 

  • 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):2395–2402

    Article  PubMed  CAS  Google Scholar 

  • Hariri N, Thibault L (2010) High-fat diet-induced obesity in animal models. Nutr Res Rev 23(2):270

    Article  PubMed  CAS  Google Scholar 

  • 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):1693–1697

    PubMed  CAS  Google Scholar 

  • 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):77–89

    Article  PubMed  CAS  Google Scholar 

  • Jump DB, Botolin D, Wang Y, Xu J, Christian B, Demeure O (2005) Fatty acid regulation of hepatic gene transcription. J Nutr 135(11):2503–2506

    PubMed  CAS  Google Scholar 

  • Jung D, Mayersohn M, Perrier D, Calkins J, Saunders R (1982) Thiopental disposition in lean and obese patients undergoing surgery. Anesthesiology 56(4):269

    Article  PubMed  CAS  Google Scholar 

  • Kasiske BL, Crosson JT (1986) Renal disease in patients with massive obesity. Arch Intern Med 146(6):1105

    Article  PubMed  CAS  Google Scholar 

  • 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):1431–1437

    Article  CAS  Google Scholar 

  • Kiang TKL, Ensom MHH, Chang TKH (2005) UDP-glucuronosyltransferases and clinical drug–drug interactions. Pharmacol Ther 106(1):97–132

    Article  PubMed  CAS  Google Scholar 

  • 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):2252–2258

    Article  PubMed  CAS  Google Scholar 

  • 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):410–416

    Article  PubMed  CAS  Google Scholar 

  • Lesser GT, Deutsch S (1967) Measurement of adipose tissue blood flow and perfusion in man by uptake of 85Kr. J Appl Physiol 23(5):621–630

    PubMed  CAS  Google Scholar 

  • 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–R237

    PubMed  CAS  Google Scholar 

  • Leykin Y, Miotto L, Pellis T (2011) Pharmacokinetic considerations in the obese. Best Pract Res Clin Anaesthesiol 25(1):27–36

    Article  PubMed  CAS  Google Scholar 

  • 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):1970–1978

    Article  PubMed  CAS  Google Scholar 

  • May DG (1994) Genetic differences in drug disposition. J Clin Pharmacol 34(9):881–897

    Article  PubMed  CAS  Google Scholar 

  • More VR, Slitt AL (2011) Alteration of hepatic but not renal transporter expression in diet-induced obese mice. Drug Metab Dispos 39(6):992–999

    Article  PubMed  CAS  Google Scholar 

  • Morrish GA, Pai MP, Green B (2011) The effects of obesity on drug pharmacokinetics in humans. Expert Opin Drug Metab Toxicol 7(6):697–706

    Article  PubMed  CAS  Google Scholar 

  • O’Rahilly S (2009) Human genetics illuminates the paths to metabolic disease. Nature 462(7271):307–314

    Article  PubMed  Google Scholar 

  • Pai MP (2010) Estimating the glomerular filtration rate in obese adult patients for drug dosing. Adv Chronic Kidney Dis 17(5):e53–e62

    Article  PubMed  Google Scholar 

  • 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):2741–2747

    Article  PubMed  CAS  Google Scholar 

  • Reiss RA, Haas CE, Karki SD, Gumbiner B, Welle SL, Carson SW (1994) Lithium pharmacokinetics in the obese. Clin Pharmacol Ther 55(4):392–398

    Article  PubMed  CAS  Google Scholar 

  • 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):1068–1076

    Article  PubMed  CAS  Google Scholar 

  • 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):308–318

    Article  PubMed  CAS  Google Scholar 

  • 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):3633–3639

    Article  PubMed  CAS  Google Scholar 

  • 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):4707–4713

    Article  PubMed  CAS  Google Scholar 

  • Speakman J, Hambly C, Mitchell S, Krol E (2007) Animal models of obesity. Obes Rev 8(s1):55–61

    Article  PubMed  Google Scholar 

  • 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):953–959

    PubMed  CAS  Google Scholar 

  • 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):739–750

    Article  PubMed  Google Scholar 

  • Wisén O, Hellström P (1995) Gastrointestinal motility in obesity. J Intern Med 237(4):411–418

    Article  PubMed  Google Scholar 

  • 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):211–218

    Article  PubMed  Google Scholar 

  • Wright R, Krinsky S, Fleeman C, Trujillo J, Teague E (1983) Gastric emptying and obesity. Gastroenterology 84(4):747

    PubMed  CAS  Google Scholar 

  • Yee J, Duffull S (2000) The effect of body weight on dalteparin pharmacokinetics. A preliminary study. Eur J Clin Pharmacol 56(4):293–297

    Article  PubMed  CAS  Google Scholar 

  • Yee GC, Lennon TP, Gmur DJ, Cheney CL, Oeser D, Deeg HJ (1988) Effect of obesity on cyclosporine disposition. Transplantation 45(3):649–650

    Article  PubMed  CAS  Google Scholar 

  • Zahorska-Markiewicz B, Jonderko K, Lelek A, Skrzypek D (1986) Gastric emptying in obesity. Hum Nutr Clin Nutr 40(4):309

    PubMed  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. College of Pharmacy and Research Institute of Pharmlaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea

    Sung-Joon Cho & Dae-Duk Kim

  2. College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, 534-729, Republic of Korea

    In-Soo Yoon

Authors
  1. Sung-Joon Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. In-Soo Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dae-Duk Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dae-Duk Kim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cho, SJ., Yoon, IS. & Kim, DD. Obesity-related physiological changes and their pharmacokinetic consequences. Journal of Pharmaceutical Investigation 43, 161–169 (2013). https://doi.org/10.1007/s40005-013-0073-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40005-013-0073-4

Keywords

Search

Navigation