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Vol. 27, Issue 11, 1350-1359, November 1999
Drug Metabolism Department, Candidate Synthesis, Enhancement, and
Evaluation, Central Research Division, Pfizer, Inc., Groton,
Connecticut
Twenty-nine drugs of disparate structures and physicochemical
properties were used in an examination of the capability of human liver
microsomal lability data ("in vitro
T1/2" approach) to be useful in the
prediction of human clearance. Additionally, the potential importance
of nonspecific binding to microsomes in the in vitro incubation milieu
for the accurate prediction of human clearance was investigated. The
compounds examined demonstrated a wide range of microsomal metabolic
labilities with scaled intrinsic clearance values ranging from less
than 0.5 ml/min/kg to 189 ml/min/kg. Microsomal binding was determined
at microsomal protein concentrations used in the lability incubations.
For the 29 compounds studied, unbound fractions in microsomes ranged
from 0.11 to 1.0. Generally, basic compounds demonstrated the greatest
extent of binding and neutral and acidic compounds the least extent of
binding. In the projection of human clearance values, basic and neutral
compounds were well predicted when all binding considerations (blood
and microsome) were disregarded, however, including both binding
considerations also yielded reasonable predictions. Including only
blood binding yielded very poor projections of human clearance for
these two types of compounds. However, for acidic compounds,
disregarding all binding considerations yielded poor predictions of
human clearance. It was generally most difficult to accurately predict
clearance for this class of compounds; however the accuracy was
best when all binding considerations were included. Overall, inclusion
of both blood and microsome binding values gave the best agreement between in vivo clearance values and clearance values projected from in
vitro intrinsic clearance data.
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