For poorly soluble drugs taken orally, what step is typically rate-limiting for absorption?

• A. Permeation across the intestinal wall
• B. Enzymatic degradation in the gut wall
• C. Dissolution in the gastrointestinal lumen
• D. First-pass metabolism in the liver

Answer: (C)

Dissolution in the gastrointestinal lumen is the rate-limiting step for absorption of poorly soluble drugs because the drug must first dissolve into the intestinal fluids before it can cross the mucosal barrier. The amount that dissolves determines the concentration of drug in solution at the absorption site, and the rate of dissolution sets how quickly a sufficient amount becomes available to permeate the intestinal wall. Once dissolved, the drug generally permeates the epithelium more readily, so permeation is not the bottleneck in this scenario. Enzymatic degradation in the gut wall can affect how much remains intact but does not typically limit the rate of absorption. First-pass metabolism in the liver affects systemic bioavailability after absorption, not the rate at which absorption occurs. Therefore, slow dissolution controls how quickly the drug is absorbed.