Presentation Description: GS-AC2 is designed as a novel and potent inhibitor of Acetyl-Coenzyme A Carboxylase (ACC) for the treatment of nonalcoholic steatohepatitis. GS-AC2 is selected to be a metabolically stable molecule and substrate of OATP transporters. It is actively transported into hepatocytes and had in vivo clearance greater than liver blood flow in monkey (1.9 L/h/kg). To elucidate the OATP-mediated liver specific delivery, GS-AC2 were orally dosed in monkey at 5 mg/kg with intravenous co-administration of rifampicin (RIF), an OATP pan-inhibitor. RIF significantly increased the systemic exposure of GS-AC2 (165-fold in AUC), suggesting OATP-mediated liver specific delivery. In contrast, when GS-AC2 was intravenously dosed with oral co-administration of RIF, the systemic exposure was not significantly altered. The use of OATP transporters and investigation in monkey are viable strategies for liver specific drug delivery. Caution is also raised that liver blood flow clearance can yield false negative outcomes of transporter inhibition.
The false negative outcomes of transporter inhibition when drug clearance is approaching to the liver blood flow.
The complete OATP inhibition in monkey can be achieved by a single IV dose of RIF.
The use of OATP transporters and investigation in monkey are viable strategies for developing liver specific drugs.