Drug Metabolism in Drug Design and Development Basic Concepts and Practice

St. John’s wort is a common herbal remedy for the treatment of depression
and contains a complex mixture of components that can be perpetrators of
drug interactions. Most common of these interactions is the enzyme induction
effects of the St. John’s wort component, hyperforin (Zhou et al., 2004).
Administration of hyperforin leads to an increase in the transcription,
translation, and enzyme activity of CYP3A4. Interactions with St. John’s
wort include: cyclosporine, oral contraceptives, midazolam, anticonvulsants,
and HMG-CoA reductase inhibitors (Izzo, 2004; Zhou, 2004). When
coadministered with these CYP3A4 substrates (victims), the plasma levels of
concomitantly administered drugs fall below their efficacious levels and
become ineffective. For example, the plasma exposure (AUC) of indinavir
when coadministered with St. John’s wort decreased by 57%. In addition, the
8 h trough concentration of indinavir fell by 81%, well below the efficacious
concentration sebsequently leading to increases in HIV RNA viral load (Piscitelli
et al., 2000). Xenobiotics, whether herbal or prescribed medicines, such as
rifampicin another potent CYP3A4 enzyme inducer, must all be carefully
assessed for their ability to alter the activity of drug-metabolizing enzymes.
In addition to the victim-perpetrator scenario where two drugs are involved,
there exists a situation where a single drug acts as both victim and perpetrator
called autoinduction. Carbamazepine (CBZ) is an anticonvulsant that causes
CYP3A4 enzyme induction in patients and this induction increases the clearance
of CBZ itself because CBZ is also a CYP3A4 substrate. In the case of CBZ, the
clearance increases from Day 1 to Day 17 (0.028 to 0.056 L/h/kg) and the steady

TABLE 5.5 Percent reduction in oral pharmacokinetic parameters due to enzyme
induction by rifampicin or St. John’s wort.

Victims

Rifampicin St. John’s wort

AUC Cmax t1/2 AUC Cmax t1/2 References

Ethinyl
estradiol

64 42 42 24 mina 48 Hall et al. (2003),
LeBel et al. (1998)
Midazolam 96 94 58 41 21 26 Backman et al. (1996),
LeBel (1998)
Cyclosporine 73 48 30 15 9 NR Bauer et al. (2003),
Hebert et al. (1992)
Statins Ac:80 A:40 A:74 Pd:71 P:74 P:min Backman et al. (2005),
Sugimoto et al. (2001)
Protease
inhibitors

Se:70 S:65 S:17 If:57 I:28/81g I:NR Grub et al. (2001),

Piscitelli (2000)

aMinimal change.
bNot reported.
cAtorvastatin.
dPravastatin.
eSaquinavir.
fIndinavir.
gPercent reduction inCmaxandC8h.

ENZYME INDUCTION 121