Intestinal excretion/secretion (IE) from the systemic circulation via the enterocytes into the intestinal lumen has traditionally been considered a minor clearance (CL) pathway. Data from a total of 91 pharmacokinetic studies employing intravenous (IV) administration in bile duct-cannulated (BDC) animals were analyzed. Fourteen compounds (15% of total compounds) exhibited >20% of IV-dosed parent in feces. Ten compounds (11%) had an IE extraction ratio (E_IE, the ratio of IE clearance over hepatic blood flow) > 0.05. It was noted that compounds with lower systemic CL have a greater propensity for a higher intestinal secretion clearance (CL_IE). It was also observed that compounds that showed high IE tended to have low/moderate passive permeability (P_app) are moderate to highly plasma bound, are substrates for an intestinal efflux transporter, and have low biliary excretion. In summary, our data show that IE can be an important route of excretion molecules for low-CL molecules.

By Murali Subramanian, Deepak Ahire, Rakshit Tanna, Zaikuan Josh Yu, Kelly Wang, Wei Wang, Gillian Smith, Xingrong Liu