Drug Metabolism in Drug Design and Development Basic Concepts and Practice

The nonlinear regression analyses with default options (automatic initial
parameter estimations with the constraints ofa>0 andb>0; no weight fit;
and iterations of 200 with the step size of 1 and the tolerance of 1e^10 ) are
initiated following selection of Finish.

Time (min)

0 10 20 30 40 50 60

R

(%

)

0

20

40

60

80

100

120

Real data

Nonlinear regression

k mint min

t k

0.0374/ , 18.5

0.693/

e 1/2

1/2 e

= =

=

(b)

Rel. amount

0 10 20 30 40 50 60

lnR

Real data

Linear regression

(a)

ke = -lnR/t

2

3

4

5

FIGURE 13.1 Semilog plot for the estimates of elimination rate constants (a), and the
direct time-concentration plot for nonlinear regression analysis (b). The semilog plots
are conventionally used to convert the exponential decay to the linear first order process
facilitating thekedetermination (a). The semilog format is no longer necessary if
nonlinear regression analysis is applied for the quantification, since ke is direct
calculated following the exponential decay model, as ist1/2(b).

TABLE 13.1 Data required forkeandt1/2determination.

t(min) 0 5 15 30 45 60
R(%) 100 85 60 30 20 10
lnR 4.61 4.44 4.09 3.40 3.00 2.30

DETERMINATION OF METABOLIC STABILITY 421