Clinical meaning
Obesity fundamentally alters drug pharmacokinetics across all four ADME phases, requiring systematic dose adjustments that cannot rely on simple total-body-weight scaling. Absorption is affected by increased splanchnic blood flow and accelerated gastric emptying in obesity, which can increase the rate of oral drug absorption for some agents, while subcutaneous drug absorption (insulin, enoxaparin, heparin) becomes unpredictable due to reduced blood flow per unit of adipose tissue and variable injection depth. Distribution is the most profoundly altered parameter: the volume of distribution (Vd) for lipophilic drugs (benzodiazepines, propofol, amiodarone, voriconazole) increases substantially because of expanded adipose tissue mass, requiring higher loading doses based on total body weight (TBW), while hydrophilic drugs (aminoglycosides, vancomycin, daptomycin) distribute primarily into lean mass with modest adipose penetration, requiring adjusted body weight (ABW = IBW + 0.4 × [TBW − IBW]) for dosing. Hepatic metabolism is altered by non-alcoholic fatty liver disease (NAFLD), which affects approximately 80-90% of individuals with severe obesity. Phase I CYP450 activity shows enzyme-specific changes: CYP3A4 activity decreases (reduced clearance of midazolam, cyclosporine, triazolam), CYP2E1 activity increases (enhanced metabolism of volatile anesthetics,...