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VOL. 73 (1), 5-26, 2007 IN VITRO INVESTIGATION OF DRUG METABOLISM AND TOXICITY...

In recent years, recombinant human P450 systems have been
increasingly used for this purpose (Figure 2). Major limitations
inherent to recombinant models are that concentrations of P450
enzymes are far in excess of their relative amount in the human
liver, and that the secondary metabolism cannot be identified.
However, such disadvantages have not appeared to hinder the utility
of cDNA expressed enzymes to P450 reaction phenotyping.
Incubating the compound with each separate recombinant P450
provides information about the role of individual P450s in metabolite
formation (32, 33-37). However, the degree of involvement of a P450
in a particular reaction in vivo can neither be estimated nor can the
metabolic profile of a drug in man be anticipated. Different strategies
based on the combined use of in vitro models showing a full
contingent of P450 enzymes (i.e. human liver microsomes, primary
human hepatocytes) and P450 recombinant models have been
proposed to mathematically reconstruct the relative contribution of
each P450 enzyme in the metabolism of a given compound (35-39).

DRUG-DRUG INTERACTIONS DUE TO ENZYME
INDUCTION/INHIBITION

Pharmacokinetic interactions occur when the disposition (i.e.
absorption, distribution, metabolism and excretion) of a drug is
altered by another (40). One of the most important pharmacokinetic
factors that control drug action is the rate of metabolic
transformation. Hence, interactions that result in changes in the
rate of drug metabolism can be of great clinical significance. Many
drugs can inhibit, induce and alter relative amounts of different
P450 enzymes. A strong inhibition/induction of P450 activities
by a molecule is expected to seriously interfere with the metabolism
of other drugs administered simultaneously or subsequently. These
changes in in vivo metabolism rates can lead drug concentrations
to fall outside their therapeutic window, implication a serious risk
of drug-drug interactions. The high cost associated with drug
development programs has focused attention on predicting,
identifying and avoiding inhibitory potential early in the discovery
process. In vitro studies, which are generally inexpensive and readily
carried out, must serve as preliminary screenings to rule out the need

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