type of drug–drug interaction is the increased incidence of failure of oral
contraceptives occurring in women who were concurrently treated with
rifampicin. A 42% decrease in the bioavailability of both ethinyl estradiol
and norethistereone, resulting in unexpected failure of contraception, was
observed in these patients, due to the induction by rifampicin of both Phase I
(primarily CYP3A4), and Phase II (UDP-glucuronosyltransferase) drug
metabolizing enzymes (LeBel et al., 1998).
The term induction, in the context of drug metabolism enzymes, is
understood to indicate the increased expression of a drug metabolizing
enzyme or enzymes in response to exposure of the cell or organism to an
exogenous or endogenous molecular inducing agent. This increased expres-
sion of the induced enzyme protein is associated with enhanced drug meta-
bolism, and is usually (but not always) the result of enhanced transcription of
the associated gene (Ronis and Ingelman-Sundberg, 1999). The phenomenon
of induction of xenobiotic metabolism has been recognized for over 40 years,
and the effects of induction on the intensity and duration of the action of
human pharmacotherapeutic agents has been an important area of pharma-
cological research for equally as long (Okey, 1990; Sueyoshi and Negishi,
2001). Although drugs may induce their own metabolism, a phenomenon
often referred to as ‘‘autoinduction,’’ induction of the metabolism of one drug
may also occur through the action of a concomitantly administered second
drug. This second type of induction constitutes one of the most common types
of drug–drug interaction, whereby one drug decreases the activity of a second
drug by enhancing its metabolism. By inducing one or more drug metabolizing
enzymes, particularly those that are relatively substrate nonspecific, a single
drug or drug candidate has the potential not only to enhance its own
clearance, but to produce drug–drug interactions with hundreds of other
therapeutic agents. The potential of a molecule to produce such drug–drug
interactions will ultimately be a majorfactor in determining its therapeutic
usefulness, and this potential should ideally be determined early on in the drug
discovery process.
Probably the most well studied paradigm for induction-based drug–drug
interactions involves the induction of one or more forms of cytochrome P450
(CYP), the superfamily of heme-thiolate proteins whose members play a
central role in hepatic and extrahepatic drug metabolism. Of all the members of
the human CYP superfamily, those of the CYP3A family, and in particular
CYP3A4, are commonly considered to have the greatest overall impact on
human pharmacotherapy. The CYP3A subfamily is the most abundantly
expressed CYP subfamily in the human liver, and CYP3A4 is known to
metabolize approximately 50–60% of all known therapeutic drugs (Luo et al.,
2004; Thummel and Wilkinson, 1998; Wrighton and Stevens, 1992). Perhaps
most important to the discussion in this chapter, the expression of CYP3A4 in
human liver can be enhanced or induced by a large number of therapeutic
drugs and other xenobiotics (Luo et al., 2004; Ronis and Ingelman-Sundberg,
1999; Sueyoshi and Negishi, 2001). CYP3A4 is not the only inducible CYP
546 TESTING DRUG CANDIDATES FOR CYP3A4 INDUCTION