title: Strategic use of plasma and microsome binding to exploit in vitro clearance in early drug discovery.
abstract: Apparent intrinsic clearance (CLia) determined from microsomal stability assays is a cornerstone in drug discovery. Categorical bins are routinely applied to this end point to facilitate analysis. However, such bins ignore the interdependent nature of apparent intrinsic microsome clearance on several ADME parameters. Considering CLia as a determinant for both metabolic stability and potential dose is more appropriate. In this context with proper accounting for nonspecific binding to microsomes and plasma, consideration of compounds with higher CLia may be warranted. The underlying benefit is the potential increase in the number of hits or chemical diversity for evaluation during the early stages of programs.
authors.affiliation: Computational ADME and Portfolio Support Group, Pharmacokinetics Dynamics and Metabolism Department, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340.
authors.forename: George
authors.initials: G
authors.lastname: Chang
authors.affiliation: Computational ADME and Portfolio Support Group, Pharmacokinetics Dynamics and Metabolism Department, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340.
authors.forename: Stefanus J
authors.initials: SJ
authors.lastname: Steyn
authors.affiliation: Computational ADME and Portfolio Support Group, Pharmacokinetics Dynamics and Metabolism Department, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340.
authors.forename: John P
authors.initials: JP
authors.lastname: Umland
authors.affiliation: Computational ADME and Portfolio Support Group, Pharmacokinetics Dynamics and Metabolism Department, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340.
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Scott
keywords: ADME parameters; Plasma binding; clearance; dose; fraction unbound; microsome binding