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 (log10CLint,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 D7.4) 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 (log10CLint,u). Overall, the majority of the model substrates
of CYP450 isoforms and already marketed drugs in our datasets exhibit
log D7.4 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.