Insights on Volume of Distribution of Acids

Acidic drugs generally have small steady-state volumes of distribution (<i>V</i>_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 <i>V</i>_ss. Enterohepatic recirculation (EHR) of parent drug or reversible acyl glucuronide can increase the <i>V</i>_ss of acids. However, rational design to incorporate EHR as a mechanism to increase <i>V</i>_ss remains challenging because of the complexity of EHR and lack of reliable predictive tools. Uptake transporters can increase the <i>V</i>_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 <i>V</i>_ss.