Table 5. Lead Optimization to Mitigate UGT-Mediated Clearance.

^aIntrinsic clearance obtained from isolated human microsomes (units = μL/min/mg).

^bIntrinsic clearance obtained from isolated human hepatocyte cells (units = μL/min/million cells).

^cIntrinsic clearance obtained from isolated cyno microsomes (units = μL/min/mg).

^dIntrinsic clearance obtained from isolated cyno hepatocyte cells (units = μL/min/million cells).

^eCynomolgus monkey, 0.5 mg/kg IV and 2.5 mg/kg PO dose. For IV and PO dosing, 29, 30, and 31 were formulated in 5% DMSO + 5% kolliphor HS 15 + 90% saline vehicle; Cl: plasma clearance after administration of single IV bolus dose.

^fCl_u: unbound in vivo clearance (in vivo cyno clearance/free fraction in cyno), free fraction calculated from plasma protein binding determined by ultracentrifugation method.