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, acetaminophen with increased risk of hepatotoxic metabolites), while CYP1A2 and CYP2C19 show variable effects. Phase II glucuronidation is generally increased, accelerating clearance of morphine, lorazepam, and acetaminophen glucuronide. Renal elimination is augmented due to obesity-related glomerular hyperfiltration, with GFR increasing 10-20 mL/min above predicted values, causing enhanced clearance of renally eliminated drugs (vancomycin, lithium, low-molecular-weight heparins) and frequently necessitating higher or more frequent dosing. Following bariatric surgery, malabsorptive procedures (Roux-en-Y gastric bypass, biliopancreatic diversion) dramatically reduce absorption of orally administered medications by bypassing the duodenum and proximal jejunum, which are the primary absorption sites for many drugs, particularly extended-release formulations, enteric-coated tablets, and medications requiring acidic gastric pH for dissolution (azole antifungals, iron, levothyroxine). Weight-based dosing strategies require selecting the correct weight scalar for each drug class: total body weight (TBW) for loading doses of lipophilic drugs, ideal body weight (IBW) for initial dosing of hydrophilic drugs with narrow therapeutic indices, adjusted body weight (ABW) for aminoglycosides and vancomycin, and lean body weight (LBW) for neuromuscular blockers and some chemotherapy protocols.