A 35-year-old man with obesity (BMI 38 kg/m²) and type 2 diabetes is started on metformin 500 mg twice daily. After 2 weeks, his plasma metformin concentration is lower than expected, and glycemic control is suboptimal. His renal function is normal (eGFR 95 mL/min/1.73m²). Which pharmacokinetic parameter is most likely responsible for the lower-than-expected plasma concentration?

Explanation

## Metformin Pharmacokinetics in Obesity ### Metformin Distribution and Clearance - **Absorption:** Oral, ~50% bioavailability; absorption site is GI tract - **Metabolism:** Minimal; NOT metabolized by liver - **Elimination:** Renal (glomerular filtration + active tubular secretion) - **Volume of Distribution (Vd):** Large; distributes extensively into tissues ### Why Plasma Concentration is Low in Obesity **Key Point:** Metformin is a hydrophilic, polar molecule that distributes into total body water and lean tissue. Obese patients have: - **Increased total body water** (relative to lean mass) - **Expanded Vd** → same dose distributed across larger volume → lower plasma concentration ### Calculation **Plasma Concentration = Dose / Vd** - Normal Vd for metformin: ~4–6 L/kg lean body weight - Obese patient: Vd increases due to expanded extracellular fluid and tissue distribution - Result: Lower steady-state plasma concentration despite normal dose ### Why This Matters Clinically - **Suboptimal glycemic control** because plasma levels are below therapeutic range - **Solution:** Dose adjustment based on actual body weight or use of extended-release formulation **Clinical Pearl:** Metformin dosing in obese patients should account for increased Vd. Some guidelines recommend dosing based on actual body weight rather than standard fixed doses.