Pharmacokinetic considerations in obesity

Using the parameters of volume of distribution and clearance, a therapeutic dosing strategy can be developed for a drug. Consequently, the effects of physiological disorders on these parameters is important for accurate pharmacotherapeutics. Regarding obesity, the volume of distribution has been shown to change in many situations. Generally, more lipophilic compounds are affected by obesity to a greater extent than hydrophilic compounds. More lipophilic compounds are associated with increases in volume of distribution in obesity; however, there are exceptions to this relationship. High LPC values did not correspond with markedly increased volumes of distribution for digoxin, procainamide, and cyclosporine. Consequently, prior knowledge of the effects of obesity on specific drugs is essential for accurate dosing strategies based upon volume of distribution; generalizations among similar groups of drugs does not always result in proper physiologic responses between obese and lean individuals. The clearance of a compound depends on the metabolic activity of characteristic enzymes that may be affected by obesity or diseases associated with obesity. Changes have been noted in both humans and animals for various CYP isozymes using either direct measurements (in animals) or through the use of metabolic markers (in humans) such as antipyrine or erythromycin. In addition, obesity has been associated with increased glucuronidation with questionable effects on sulfation. Changes between obese and lean subjects have also been observed for antioxidant systems including glutathione and catalase. It is important to note the variability in characterizing metabolic changes in obesity. Given the numerous possible genetic and environmental influences, predicting changes in metabolic activity can be difficult. Furthermore, there are possibilities that similar concentrations of a drug at its site of action may not elicit a similar response between obese and lean subjects, thereby making accurate therapeutic modifications more difficult for obese individuals. Renal function, particularly glomerular filtration, has been shown to change with obesity. Increased glomerular filtration in some studies has been contradicted by decreases in glomerular filtration in other studies. These discrepancies illustrate the possible ramifications of different degrees of obesity, with morbidly obese individuals exhibiting different responses than moderately obese individuals. The effects of obesity on the toxicology of specific compounds is questionable depending upon not only the presence of enzymes that create toxic metabolites, but also depending upon the presence of enzymes that remove toxic metabolites from the body. In conclusion, a safe therapeutic protocol for obese individuals should be based upon existing therapeutic information as well as careful monitoring of the patient during pharmacologic intervention.