effects for a drug with a narrow therapeutic window. With the expectation to
harmonize and/or standardize clinical DDI studies, a minimal best practice for
in vivo CYP inhibition-mediated DDIs has been proposed, and a list of
common CYP substrates and inhibitors for clinical DDI studies is shown in
Table 5.4 (Bjornsson, 2003; Tucker et al., 2001).In vitroCYP inhibition data
are important for selecting appropriate CYP probe substrates and inhibitors as
well as guiding DDI study designs. Often, clinical DDI studies are conducted in
healthy volunteers. However, depending on the therapeutic indication or
mechanism of clearance, clinical DDI studies can also be conducted with
specific subpopulations of subjects, such as patients with cancer, HIV infection,
hepatic or renal impairment. Studies with genotyped subjects (e.g., CYP2D6,
CYP2B6, CYP2C9, and CYP2C19) are also possible.
5.3 Enzyme Induction
5.3.1 Enzyme and Pharmacokinetic Changes
Enzyme induction or the process of creating excess enzyme in a biological
system can give rise to pharmacokinetic situations whereby drug interactions
occur. To fully understand the fundamental mechanism by which greater
concentrations of enzyme can cause pharmacokinetic disequilibrium, we must
describe the concept of intrinsic clearance. The maximum rate of metabolic
clearance is the ratio ofVmax/Kmreferred to as intrinsic metabolic clearance
(derived from M–M kinetics and assuming [substrate]<Km) (Rowland, 1988).
Kmis a constant for any enzyme–substrate pair, however,Vmaxis a composite
term with enzyme concentration being a variable:Vmax=kcat [E]T, wherekcat
is the catalytic constant and [E]Tis the total concentration of enzyme (Segel,
1993). In most cases, induction does not cause a change inKmorkcat. Under
normal situations, the pool of total enzyme exists in equilibrium between the
constitutive production and degradation of enzyme. When greater amounts of
enzyme are produced and the degradation rate of enzyme does not change, the
total pool of enzyme concentration increases (i.e., [E]Tincreases) and the
intrinsic metabolic clearance increases. Whereas the overall hepatic metabolic
clearance of a drug is a function of blood flow, unbound drug concentration,
and intrinsic clearance; increasing the intrinsic clearance elevates the overall
hepatic elimination of a drug (Rowland, 1988).
Pharmacokinetically, the victims of enzyme induction generally demonstrate
reduced AUC,Cmax, trough concentrations, and half-life as a reflection of
increased clearance. Table 5.5 illustrates several perpetrators and victims of
CYP3A4 enzyme induction and the effects on pharmacokinetic parameters. In
each of the cases illustrated in Table 5.5, there are significant biological
consequences to a reduction in exposure. For example, reduced ethinyl
estradiol levels can lead to unexpected pregnancies and reduced cyclosporine
levels can lead to organ transplant rejection.
120 METABOLISM-MEDIATED DRUG–DRUG INTERACTIONS