state plasma concentrations of CBZ decline over this period, reaching a lower
plateau after several weeks (Bertilsson et al., 1980; Eichelbaum et al., 1975). After
the autoinduction phase has reached its lower plateau, doses of CBZ are then
readjusted (increased) to achieve new efficacious concentrations of drug.
Autoinduction is a phenomenon that can occur anytime a drug induces an
enzyme that is also predominately involved in its own metabolic clearance.
5.3.2 Mechanisms of Enzyme Induction
There are two general mechanisms by which enzyme induction occurs;
stabilization of mRNA (or enzyme) or increased gene transcription (Okey,
1992). Induction of CYP2E1 is an example where enzyme stabilization is known
to occur and results in increased activity due to a decrease in enzyme
degradation (Chien et al., 1997). However, the most common mechanism of
CYP enzyme induction is transcriptional gene activation. Transcriptional
activation is mediated via nuclear receptors (NRs) that function as transcription
factors, such as aromatic hydrocarbon receptor (AhR) (Mandal, 2005),
constitutive androstane receptor (CAR) (Qatanani and Moore, 2005), farnesoid
X receptor (FXR) (Westin et al., 2005), and pregnane X receptor or SXR-
steroid X receptor (PXR) (Honkakoski et al., 2003; Mangelsdorf et al., 1995;
Moore et al., 2002; Tirona and Kim, 2005; Wang and LeCluyse, 2003). These
NRs are activated either through ligand (drug) binding or other mechanisms of
activation, such as regulation of coactivators or corepressors. Table 5.6
illustrates several NRs, their target genes, and common human activators. A
more comprehensive list of target genes can be found in recent reviews
(Handschin and Meyer, 2003; Puga et al., 2000; Wang and LeCluyse, 2003).
The general concept for NR signaling is that in the absence of a ligand, the
NR is associated with NR corepressor complexes, conferring a basal level of
transcription. Ligand binding to the ligand binding domain (LBD) of the NR
induces conformational changes that lead to the release of corepressors and
recruitment of coactivators (Glass et al., 1997; Glass and Rosenfeld, 2000;
Mangelsdorf and Evans, 1995). The LBDs of many NRs are different among
various animal species, especially between laboratory animals and humans
(Blumberg et al., 1998; LeCluyse, 2001b; Moore et al., 2002). Therefore,in vitro
animal orin vivoanimal models of enzyme induction can be misleading and are
generally not employed to study or predict the potential induction effect in
humans. With PXR as an example, recruitment of coactivators and the
dimerization partner retinoid X receptor (RXR) contributes to chromatin
remodeling and subsequent transcriptional activation via specific response
elements (RE) that consist of a core DNA consensus sequence that can be
configured into a variety of structured motifs (Blumberg, 1998; Tirona and Kim,
2005). Regulation is achieved by the binding of the NR complex through the
DNA binding domain (DBD) to their respective RE present in the promoter
region of target genes (drug-metabolizing enzymes or drug transporters). This
process is illustrated in Fig. 5.3, using PXR as an example. PXR, which resides in
122 METABOLISM-MEDIATED DRUG–DRUG INTERACTIONS