Drug Metabolism in Drug Design and Development Basic Concepts and Practice

The typical results of such an analysis, in which the data in Table 13.1 were
used, are shown in Table 13.2.

Intrinsic Clearance

i. Intrinsic clearance (CLint), the key parameter for in vitro–in vivo

correlation, can be directly derived from in vitro t1/2 (Obach et al.,

1997; Reddy et al., 2005; Slaughter et al., 2003; Zhao et al., 2005):

CLint¼keSF;or

CLint¼ 0 : 693 =t 1 = 2 SF: ð 13 : 3 Þ

If liver microsomal preparations are used as the enzyme source,

SF¼ðGmicrs=WliverÞðWliver=WbodyÞ=Cprotein; with

SF, scaling factor (mL/kg);Gmicrs, the average quantity of microsomal

protein in the liver (mg),Wliver, liver weight (g);Wbody, body weight (kg);

andCprotein, protein concentration in the reaction mixture (mg/mL).

Gmicrs/Wliveris usually considered to be around 50 mg/g (Iwatsubo et

al., 1997), whileWliver/Wbodyis approximately 20 g/kg in humans; thus,

CLint¼ 10000 : 693 =ðt 1 = 2 CproteinÞ¼ 693 =ðt 1 = 2 CproteinÞ;in units of mL=min=kg;

or,

CLint¼ 0 : 693 =ðt 1 = 2 CproteinÞin units of L=min=kg: ð 13 : 4 Þ

TABLE 13.2 Results of nonlinear regression analysis forkeandt1/2determination.

Equation: Single exponential decay (y=aexp(bx))
rr^2 ab
0.999 0.997 101.3 0.037
(P<0.0001) (P<0.0001)
Regression
DF SS MS FP
1 6702.5 6702.5 1464.5 <0.0001
Statistical test
Normality Constant variance
Pass Pass
Kinetic parameter
ke t1/2(min)
0.037 18.7

422 DETERMINATION OF METABOLIC RATES AND ENZYME KINETICS