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Acidic drugs generally have small steady-state volumes of distribution (<i>V</i><sub>ss</sub>) 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><sub>ss</sub>. Enterohepatic recirculation (EHR) of parent drug or reversible acyl glucuronide can increase the <i>V</i><sub>ss</sub> of acids. However, rational design to incorporate EHR as a mechanism to increase <i>V</i><sub>ss</sub> remains challenging because of the complexity of EHR and lack of reliable predictive tools. Uptake transporters can increase the <i>V</i><sub>ss</sub> 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><sub>ss</sub>.
Published in: Journal of Medicinal Chemistry
Volume 68, Issue 16, pp. 16901-16911