Drug Metabolism in Drug Design and Development Basic Concepts and Practice

compounds. However, the outcomes of such remedies have been mixed,
providing one of the current challenges forin vitro–in vivocorrelations (Shibata
et al., 2000; Soars et al., 2002).

13.5.2.2 In vivo Prediction Hepatic clearance (CLh) in the well-stirred
model can be expressed as

CLh¼QhCLintfu=ðQhþCLintfuÞ: ð 13 : 14 Þ

Thus,

Fh¼ 1 CLh=Qh¼ 1 =ð 1 þCLintfu=QhÞð 13 : 15 Þ

Eh¼ 1 Fh¼ 1 =½ 1 þQh=ðCLintfuފ: ð 13 : 16 Þ

If CLintis determined in vitro and iffu is known, the important PK
parameters (CLh,Fh, andEh) can be directly estimated using Eq. 13.14–13.16,
assuming thatQhis constant, that is, 1.5 L/min, or approximately 21 mL/min/
kg for humans (Davies and Morris, 1993). Moreover, if nonspecific protein
binding in thein vitroassay systems is factored into the equations,fushould be
replaced byfu=fu

0

, wherefu

0
is the unbound fraction in thein vitrometabolic
systems, which can be determined using equilibrium dialysis (Soars et al.,
2002). Therefore, Eq. 13.14 can be expressed as

CLh¼QhCLintfu=fu

0

=ðQhþCLintfu=fuÞ: ð 13 : 17 Þ

For many drugs, clearance from the body is due mainly to liver metabolism
and renal excretion:

CLT¼CLhþCLr

where CLTand CLrare total body and renal clearances, respectively. CLris
usually determinedin vivousing urinary excretion and blood concentration
data for the parent compound.
If the compound is being developed for oral administration,

CLpo¼CLT=ðFhfaÞ¼ðCLhþCLrÞ=ðFhfaÞ

wherefais the fraction absorbed into the portal vein from the small intestine,
and is equal to 1 if the compound is completely absorbed. In the case of the
high hepatic clearance with negligible urinary excretion of the parent
compound,

CLpo¼CLh=ðFhfaÞ¼CLintfu=fa or ð 13 : 18 Þ

CLpo¼CLintfu=fu

0

=fa ð 13 : 19 Þ

AUCpo¼Dose=ðCLintfu=fu

0

=faÞ: ð 13 : 20 Þ

PREDICTION OF HUMAN HEPATIC CLEARANCE 437