Obesity

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Recent reports indicate that obesity in the United States and worldwide is on the rise [70]. Body mass index (BMI) is used to define obesity. Body mass index is the ratio of the weight in kilograms to the square of the height in meters [71]. The prevalence of childhood obesity has doubled in the last two decades [72]. Estimates suggest that about 16% of children in the United States may be obese. These estimates are higher in some minorities. Blounin and Waren define obesity as a disease state characterized as a condition from excess accumulation of body fat. Obesity is associated with changes in plasma protein binding constituents and increase in adipose tissue mass and lean body mass, organ mass, cardiac output, and splanchnic blood flow relative to normal weight individuals [73].

Absorption in obesity is poorly understood, overall no significant absorption differences in the obese compared to lean subjects have been reported. For obese patients, drugs with less lipophilicity have little or no change in VD. Increasingly lipophilic substances are affected by obesity. Drugs predominantly bound to albumin do not show any significant difference in protein binding [74-76]. AGP concentrations maybe higher in obese patients resulting in decreased free fractions [77].

The effect of obesity on metabolism has not been well studied. The activity of C4P3A4 is lower and that of CYP2E1 is higher in obese compared to nonobese [78]. The effect of obesity on cytochrome P450 1A2, 2C9, 2C19, and 2D6 is inconclusive. Glucoronidation is significantly increased and Sulfation may be moderately increased in obese [79, 80]. For excretion, GFR has been shown to increase [81, 82] in some citations, whereas it has also been shown to decrease [83]. This discrepancy has been hypothesized to be due to different degrees of obesity in different studies. Tubular secretion is possibly increased and tubular reabsorption is decreased in obese [80, 84, 85].

Georgiadis et al. [86] assessed toxicity of several chemotherapeutic agents to obese and compared toxicity to nonobese patients and concluded that there was no correlation between toxicity and obesity. Each drug behaved differently so predication of toxicity based on obesity was difficult. Therefore, careful monitoring of narrow therapeutic index has been recommended. When the same dose of triazolam [87, 88] was administered, obese patients showed increased sensitivity. Desensitization of acetylcholine receptors has been observed in obese [87].

With the incidence of obesity on the rise, it may become increasingly important to assess obesity as a covariate during drug development.

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