The volume of distribution is an indicator of poor in vitro–in vivo extrapolation of clearance for acidic drugs in the rat

Abstract

1. We applied the regression offset approach to predict rat in vivo intrinsic clearance (CL_int) for 54 new chemical acid entities with high plasma protein binding values and low renal clearance (CL). The prediction success was correlated to volume of distribution (V_d), molecular weight (Mw) and CL.

2. A correlation between poor in vitro–in vivo extrapolation (IVIVE) and V_d values distinct from the V_d of albumin (0.1–0.2 L/kg) was revealed. For compounds with a V_d value above 0.5 L/kg, 0% of the predictions of in vivo CL_int was within twofold of the observed value, compared to 69% for compounds with a V_d value below 0.5 L/kg.

3.  Compounds with a Mw below 450 g/mol demonstrated more accurate in vivo CL_int predictions than compounds with a Mw above 450 g/mol, i.e. 63% compared to 21% within twofold. For compounds with in vivo CL below 30% of the liver blood flow (LBF), 53% of the predictions was within twofold of the observed value, compared to 0% for compounds with CL above 30% of the LBF.

4. We show that accurate IVIVE for acidic compounds with high plasma protein binding and low renal CL can be associated with a low V_d (i.e. around the V_d of albumin) and with a low in vivo CL, and that Mw is an important optimization parameter for pharmacokinetic. This study also further demonstrates the advantages of the application of the regression method for identifying cases when metabolic CL is not the single major elimination pathway.

• Acids
• CL_int
• hepatocytes
• in vitro to in vivo scaling
• liver
• metabolism
• regression offset
• volume of distribution