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Effect of Obesity on the Pharmacokinetics of Drugs in Humans

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Abstract

The prevalence of obesity has dramatically increased in recent years and now includes a significant proportion of the world’s children, adolescents and adults. Obesity is linked to a number of co-morbidities, the most prominent being type 2 diabetes mellitus. While many agents are available to treat these conditions, the current knowledge regarding their disposition in the obese remains limited.

Over the years, both direct and indirect methodologies have been utilized to assess body composition. Commonly used direct measures include underwater weighing, skinfold measurement, bioelectrical impedance analysis and dual-energy x-ray absorptiometry. Unfortunately, these methods are not readily available to the majority of clinicians. As a result, a number of indirect measures to assess body composition have been developed. Indirect measures rely on patient attributes such as height, bodyweight and sex. These size metrics are often utilized clinically and include body mass index (BMI), body surface area (BSA), ideal bodyweight (IBW), percent IBW, adjusted bodyweight, lean bodyweight (LBW) and predicted normal weight (PNWT).

An understanding of how the volume of distribution (Vd) of a drug changes in the obese is critical, as this parameter determines loading-dose selection. The Vd of a drug is dependent upon its physiochemical properties, the degree of plasma protein binding and tissue blood flow. Obesity does not appear to have an impact on drug binding to albumin; however, data regarding α1-acid glycoprotein binding have been contradictory. A reduction in tissue blood flow and alterations in cardiac structure and function have been noted in obese individuals. At the present time, a universal size descriptor to describe the Vd of all drugs in obese and lean individuals does not exist.

Drug clearance (CL) is the primary determinant to consider when designing a maintenance dose regimen. CL is largely controlled by hepatic and renal physiology. In the obese, increases in cytochrome P450 2E1 activity and phase II conjugation activity have been observed. The effects of obesity on renal tubular secretion, tubular reabsorption, and glomerular filtration have not been fully elucidated. As with the Vd, a single, well validated size metric to characterize drug CL in the obese does not currently exist. Therefore, clinicians should apply a weight-normalized maintenance dose, using a size descriptor that corrects for differences in absolute CL between obese and non-obese individuals.

The elimination half-life (t½) of a drug depends on both the Vd and CL. Since the Vd and CL are biologically independent entities, changes in the t½ of a drug in obese individuals can reflect changes in the Vd, the CL, or both.

This review also examines recent publications that investigated the disposition of several classes of drugs in the obese — antibacterials, anticoagulants, antidiabetics, anticancer agents and neuromuscular blockers.

In conclusion, pharmacokinetic data in obese patients do not exist for the majority of drugs. In situations where such information is available, clinicians should design treatment regimens that account for any significant differences in the CL and Vd in the obese.

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Acknowledgements

This work was supported in part by grant no. AG-017880 from the US Department of Health and Human Services. The authors have no conflicts of interest that are directly relevant to the content of this review.

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  1. Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts Medical Center, 136 Harrison Avenue, Boston, Massachusetts, 02111, USA

    Michael J. Hanley &  David J. Greenblatt

  2. United States Pharmacopeia, Rockville, Maryland, USA

    Darrell R. Abernethy

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  1. Michael J. Hanley
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Hanley, M.J., Abernethy, D.R. & Greenblatt, D.J. Effect of Obesity on the Pharmacokinetics of Drugs in Humans. Clin Pharmacokinet 49, 71–87 (2010). https://doi.org/10.2165/11318100-000000000-00000

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