Clinical Consequences of Altered Drug Disposition in Obesity
Journal of Clinical Trials

Journal of Clinical Trials
Open Access

ISSN: 2167-0870

+44 20 3868 9735

Editorial - (2012) Volume 2, Issue 4

Clinical Consequences of Altered Drug Disposition in Obesity

Romi Ghose*
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, USA
*Corresponding Author: Romi Ghose, Department of Pharmacological and Pharmaceutical Sciences, University of Houston, USA, Tel: 713-795-8343, Fax: 713-795-8305 Email:

Obesity is a major health problem in the United States and worldwide. About 30% of the population in the US is obese (Body Mass Index [BMI]>30 kg/m2), while ~5% of the population is morbidly obese (BMI >40 kg/m2) [1,2]. Obesity and morbid obesity are associated with changes in metabolism and clearance of drugs. This can increase the risks of adverse drug reactions and drug-drug interactions in obese individuals.

Alterations in drug metabolism in obese individuals were reported in the early eighties. Drug metabolism is primarily regulated by the Drug Metabolizing Enzymes (DMEs), which are broadly classified into phases I and II. Phase I DMEs primarily comprise of the Cytochrome (CYP) 450 family of enzymes. CYP3A4 is the most common isoform expressed in human liver and metabolizes ~50% of known drugs [3,4]. Phase II metabolism consists of conjugation reactions such as glucuronidation, sulfation, glutathione conjugation or methylation forming polar metabolites leading to enhanced excretion [4].

Obesity was associated with significantly lower metabolism of the CYP3A4-substrates, N-methyl-erythromycin and triazolam, indicating reduced CYP3A4 metabolic activity [5-7]. Other CYP3A4-metabolized drugs such as carbamazepine, alfentanil and taranabant were also reduced in obese patients compared to their non-obese counterparts [8-10]. Obesity associated changes in drug metabolism by other CYP isoforms have also been reported. For e.g. increased metabolism of chlorzoxazone (CYP2E1 substrate) to 6-hydroxychlorzoxazone was observed in obese individuals. This was attributed to increased CYP2E1 activity associated with obesity [11]. CYP2D6-mediated metabolism of nebivolol was increased [12], while CYP1A2-mediated theophylline metabolism was decreased [13] in obese individuals compared to nonobese individuals. In obese patients, clearances of oxazepam and lorazepam, (widely used benzodiazepines and excreted as glucuronide conjugates) were significantly increased [14]. The authors attributed this to increased UGT activity in obese individuals. Thus, the effects of obesity on the metabolism of drugs may depend on the enzymatic pathway.

Several studies in animal models of obesity have shown that expression of DMEs is altered in obesity. For e.g. altered gene expression of DMEs in genetically obese zucker fatty rats (reduction in CYP2B1/2 and Mrp3) and leptin-resistant (db/db) mice (increase in CYP2B10) have been reported [15,16]. Cyp3a11 gene and protein expression were significantly reduced in both long-term (12 weeks) and short-term treatment (1 week) of high fat diet (HFD, 60% kcal from fat) [16]. On the other hand, gold thioglucose induced obese mice had significant elevations in Cyp2b1 and Cyp4a10 gene expression [16]. We recently showed that mRNA levels of the phase II DMEs (Ugt1a1, Sult1a1, Sultn) were reduced ~30-60% in mice fed HFD (60% kcal fat for 14 weeks) compared to low fat diet (LFD, 10% kcal fat) mice [17]. Cyp2e1 and Cyp1a2 expression were unaltered in HFD mice, while Cyp3a11 expression was reduced [17]. This caused disparities in the Pharmacodynamics (PD) of midazolam, CYP3A substrate, (increased sleep time) and zoxazolamine, CYP2E1 substrate (no change in sleep time) in HFD mice [17]. These findings indicate that regulation of CYPs is dependent on the model of obesity and is tissue-, isoform- and species-specific.

The mechanism underlying changes in drug metabolism/ clearance in obesity is not known. Among other factors, obese patients have relatively more fat, and less lean tissue per kilogram of total body weight than lean individuals. Blood volume is also increased, particularly in morbidly obese individuals [18]. In addition, obese patients were shown to suffer from chronic, low-grade inflammation. Release or over-expression of TNF-α and C-reactive protein in adipose tissue of obese individuals have been reported [19,20]. However, the role of inflammation in regulation of DMEs and transporters in obesity remains unclear. All these and other factors can contribute to alterations in drug disposition in obese individuals.

The kidneys are the primary organs involved in the elimination of drugs. Elimination of drugs through the kidneys involves glomerular filtration, tubular secretion and tubular re-absorption. The exact effect of obesity on these functions is not fully understood. Clearance of renally eliminated drug was found to be higher in obese patients because of increased glomerular filtration and tubular secretion. However, the influence of obesity on the tubular re-absorption is not known.

Future clinical trials should put emphasis on assessing the impact of obesity on the pharmacokinetics of the particular drug, as well as the enzymes involved in the metabolism and clearance process. Furthermore, the molecular mechanism underlying the changes in the metabolism and elimination of the drug in obesity needs to be elucidated. This will enable the extrapolation of the results to other drugs which are eliminated by the same pathway. Future research should focus on individual metabolic and elimination pathways in adults and children that are altered in obese individuals compared to their non-obese counterparts. Most studies have been conducted in the adult population, with very limited information on the metabolism and clearance of drugs in obese children. Currently, findings from obese adults are extrapolated to obese children, as clinical studies in obese children are not available. Studies have shown differences in expression and activity of drug metabolizing enzymes, glomerular filtration and tubular processes, blood flow etc. among obese and non-obese patients. Impact of obesity on drug metabolism and elimination greatly differs per drug metabolic or elimination pathway.

Most of the studies so far have been conducted in over-weight or moderately obese individuals (~30 kg/m2). Future studies need to include morbidly obese (BMI>40 kg/m2) and super-obese (BMI>50 kg/ m2) patients in these studies.

Since prevalence of obesity is increasing world-wide, it is critical to assess the impact of obesity on drug safety and efficacy in obese children and adults. This will lead to the development of rational approaches to counteract undesirable effects of drugs in these individuals. Ultimately, this will increase the safety of drugs in individual patients.


  1. Flegal KM, Carroll MD, Ogden CL, Curtin LR (2010) Prevalence and trends in obesity among US adults, 1999-2008. JAMA 303: 235-241.
  2. Nebert DW, Russell DW (2002) Clinical importance of the cytochromes P450. Lancet 360: 1155-1162.
  3. Meyer UA (1996) Overview of enzymes of drug metabolism. J Pharmacokinet Biopharm 24: 449-459.
  4. Hunt CM, Westerkam WR, Stave GM, Wilson JA (1992) Hepatic cytochrome P-4503A (CYP3A) activity in the elderly. Mech Ageing Dev 64: 189-199.
  5. Hunt CM, Watkins PB, Saenger P, Stave GM, Barlascini N, et al. (1992) Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol. Clin Pharmacol Ther 51: 18-23.
  6. Abernethy DR, Greenblatt DJ, Divoll M, Smith RB, Shader RI (1984) The influence of obesity on the pharmacokinetics of oral alprazolam and triazolam. Clin Pharmacokinet 9: 177-183.
  7. Li XS, Nielsen J, Cirincione B, Li H, Addy C, et al. (2010) Development of a population pharmacokinetic model for taranabant, a cannibinoid-1 receptor inverse agonist. AAPS J 12: 537-547.
  8. Caraco Y, Zylber-Katz E, Berry EM, Levy M (1995) Carbamazepine pharmacokinetics in obese and lean subjects. Ann Pharmacother 29: 843-847.
  9. Kharasch ED, Russell M, Mautz D, Thummel KE, Kunze KL, et al. (1997) The role of cytochrome P450 3A4 in alfentanil clearance: implications for interindividual variability in disposition and perioperative drug interactions. Anesthesiology 87: 36-50.
  10. O'Shea D, Davis SN, Kim RB, Wilkinson GR (1994) Effect of fasting and obesity in humans on the 6-hydroxylation of chlorzoxazone: a putative probe of CYP2E1 activity. Clin.Pharmacol. Ther 56: 359-367.
  11. Cheymol G, Woestenborghs R, Snoeck E, Ianucci R, Le Moing JP, et al. (1997) Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects. Eur J Clin Pharmacol 51: 493-498.
  12. Zahorska-Markiewicz B, Waluga M, Zielinski M, Klin M (1996) Pharmacokinetics of theophylline in obesity. Int J Clin Pharmacol Ther 34: 393-395.
  13. Abernethy DR, Greenblatt DJ, Divoll M, Shader RI (1983) Enhanced glucuronide conjugation of drugs in obesity: studies of lorazepam, oxazepam, and acetaminophen. J Lab Clin Med 101: 873-880.
  14. Yoshinari K, Takagi S, Sugatani J, Miwa M (2006) Changes in the expression of cytochromes P450 and nuclear receptors in the liver of genetically diabetic db/db mice. Biol Pharm Bull 29: 1634-1638.
  15. Yoshinari K, Takagi S, Yoshimasa T, Sugatani J, Miwa M (2006) Hepatic CYP3A expression is attenuated in obese mice fed a high fat diet. Pharm Res 23: 1188-1200.
  16. Ghose R, Omoluabi O, Gandhi A, Shah P, Strohacker K, et al. (2011) Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters. Life Sci 89: 57-64.
  17. Alexander JK, Dennis EW, Smith WG, Amad KH, Duncan WC, et al. (1962) Blood volume, cardiac output, and distribution of systemic blood flow in extreme obesity. Cardiovasc Res Cent Bull Winter 1: 39-44.
  18. Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity linked insulin resistance. Science 259: 87-91.
  19. Wellen KE, Hotamisligil GS (2005) Inflammation, stress, and diabetes. J Clin Invest 115: 1111-1119.
Citation: Ghose R (2012) Clinical Consequences of Altered Drug Disposition in Obesity. J Clin Trials 2:e107.

Copyright: © 2012 Ghose R. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.