Lipophilic Metabolic Efficiency (LipMetE) and Drug Efficiency Indices to Explore the Metabolic Properties of the Substrates of Selected Cytochrome P450 Isoforms

Cytochrome P450 (CYP450) enzymes belong to a superfamily of heme-containing proteins that are involved in the metabolism of structurally diverse endogenous and exogenous compounds. Various proof-of-concept studies indicate that metabolic stability and intrinsic clearance of CYP450 substrates are linked with the respective lipophilicity (log  P or log  D ). This necessitates the normalization of lipophilicity (log  P or log  D ) of a given CYP450 substrate with respect to its metabolic stability (LipMetE) and intrinsic clearance (log 10 CL int,u ). Therefore, in this article, the LipMetE values of already known substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, including some marketed drugs, have been calculated to elucidate the relationship between lipophilicity (log  D 7.4 ) and in vitro clearance. Moreover, various drug efficiency metrics including lipophilic efficiency (LipE) and ligand efficiency (LE) have been evaluated, and the thresholds of these parameters have been defined for the CYP450 substrates exhibiting normalized LipMetE. Our results indicate that for a given range of LipMetE, greater the log  D value of the substrate the more avidly it binds to a given CYP450 enzyme and shows more intrinsic clearance (log 10 CL int,u ). Overall, the majority of the model substrates of CYP450 isoforms and already marketed drugs in our datasets exhibit log  D 7.4 values of ∼2.5 with LipMetE values in the range of 0-2.5 and LipE values of ≤3. Overall, consideration of these parameters in ADME profiling could aid in reducing the drug failure rate in the later stages of clinical investigations.