Reactive Metabolites or Intermediates Reactive metabolites are chemically
unstable and often rapidly bind to proteins or glutathione (GSH). In general,
GSH adducts are not present at significant levels in circulation, because they
undergo rapid elimination via direct biliary excretion or further metabolism to
mercapturic acids that are excreted into urine. Reactive metabolites can be
monitored via quantitative analysis of their GSH adducts or mercapturic acids in
excreta. However, it is not practical to test the toxicity of reactive metabolites on
animals directly since the synthesis and dosing preparation of reactive
metabolites are extremely difficult or impossible due to their chemical instability
(Davis-Bruno and Atrakchi, 2006).
7.4 Drug–Drug Interaction Studies
Drug interactions are part of the assessment of drug safety and effectiveness. In
the past, adverse pharmacokinetic drug interactions were one of the most
frequent reasons that the drugs failed in drug development or needed to be
withdrawn from markets (Prentis et al., 1988). The failure related to drug
interactions/drug metabolism in drug development has been greatly reduced in
the United States since the FDA issued the guidance forin vitrodrug metabolism
studies in 1997 and the guidance forin vivodrug interaction studies in 1999 (Kola
and Landis, 2004). Now industry sponsors address issues of drug metabolism and
drug interactions in the early phase drug development. Interactive dialogues
between the regulatory agencies and sponsors have generated a positive impact
on new drug development programs. The lessons learned from past experiences
have helped in both regulatory agencies and industry sponsors understand the
potential consequences of incomplete understanding and the necessary measures
needed to minimize risk resulting from severely harmful drug interactions. A risk
management plan has to be considered when a new, strong CYP inhibitory drug
is being developed for oral administration, especially when CYP3A4 is the
isoform that is affected. The understanding of the potential for drug–drug
interaction continues to advance with more knowledge about drug transporters
(Kim, 2006), emergence of the role of CYP2C8 (Totah and Rettie, 2005), the
classification of CYP inhibitors, among others. Recently, the FDA issued its
latest draft guidance for drug interaction studies (FDA, 2006a). In addition, the
agency has listed on its Web site more detailed information regarding the selec-
tion of CYP substrates and inhibitors and the experimental design for studying
effects on transporters (http://www.fda.gov/cder/drug/drugInteractions/
default.htm-overview). In this section, the main focus is on special considera-
tions in the conduct of drug interaction studies.
7.4.1 General Strategies
Drug interaction studies should be planned in the early exploratory phase of
drug development. Thein vivostudies should be conducted according to the
218 REGULATORY CONSIDERATIONS OF DRUG METABOLISM AND DRUG