Insights on Volume of Distribution of Acids

Acidic drugs generally have small steady-state volumes of distribution (V_ss) around 0.1-0.25 L/kg, due to high binding to serum albumin and low binding to phospholipids in tissues. Acids can reach pharmacological targets in tissues despite small V_ss. Enterohepatic recirculation (EHR) of parent drug or reversible acyl glucuronide can increase the V_ss of acids. However, rational design to incorporate EHR as a mechanism to increase V_ss remains challenging because of the complexity of EHR and lack of reliable predictive tools. Uptake transporters can increase the V_ss of acidic drugs by increasing the liver drug concentration and can facilitate EHR through enhancing biliary elimination and glucuronide formation. Half-life extension of acids mainly relies on reducing clearance or using modified release formulations rather than modulating V_ss.