15.7.4 Specialized Clinical Studies
Clinical studies may be conducted to further evaluate the impact of metabolism via a
polymorphic enzyme or to establish a clinical drug–drug interaction risk assessment.
The venlafaxine study described below provides a recent example of
polymorphic reaction phenoyping. A major route of venlafaxine metabolism
(O-demethylation) was identifiedin vitroas being mediated by CYP2D6 using
microsomes from both poor and extensive metabolizers of CYP2D6 (Otton
et al., 1996). Subsequently, a clinical study was conducted to evaluate the
metabolism of venlafaxine in poor and extensive metabolizers of CYP2D6 with
and without a low dose of quinidine (CYP2D6 inhibitor) (Lessard et al., 1999).
In the absence of quinidine, the oral clearance of venlafaxine in the poor
CYP2D6 metabolizers was fourfold less than for the extensive metabolizers. In
the presence of quinidine, the oral clearance of venlafaxine in the extensive
CYP2D6 metabolizers was approximately fivefold less than in the absence of
quinidine with a decrease in the formation ofO-desmethyl-venlafaxine (CYP2D6
mediated pathway). In poor CYP2D6 metabolizers quinidine did not affect the
oral clearance or the metabolic clearance of venlafaxine to its metabolites.
Clinical drug–drug interactions studies will be discussed in Chapter 5.
15.8 Summary and Future Directions
Reaction phenotyping for P450 metabolism is well established and has become
a routine technique in the early discovery evaluation for NCEs. For non-P450
enzymes, reaction phenotyping is usually focused on answering specific
mechanistic questions that arise during the drug development process.
Designing effective reaction phenotyping studies requires a thorough under-
standing of the enzyme of interest (i.e., the enzyme’s substrate specificity,
mechanism of reaction catalysis, tissue expression level, subcellular location,
required cofactors/experimental conditions, and selective inhibitors) in
addition to the ‘‘appropriate tools.’’
As technology continues to progress in the science of reaction phenotyping,
particularly for the non-P450 enzymes, it will enhance our ability to move
compounds forward in the drug development process with the confidence that
clinically significant interindividual variability in pharmacokinetics due to
either significant polymorphic metabolism or drug–drug interactions can be
avoided or hopefully minimized.
Acknowledgments
The authors would like to acknowledge the kind assistance of Ms. Theresa Davis
and Mr. Michael Zientek in the preparation of this manuscript. Figure 15.5 was
graciously supplied by Dr. Ruth Hyland and Blackwell Publishing.
504 REACTION PHENOTYPING