The pharmacokinetic and metabolic evaluation of a single oral and IV dose
of sildenafil (see Section 15.6.4.4 forin vitroreaction phenotyping data) in
humans is an example of a quantitative radiolabeled ADME study (Muirhead
et al., 2002). No unchanged drug was recovered from the urine or feces
indicating that metabolism is the major route of elimination for sildenafil. The
principal routes of metabolism were identified (N-demethylation, multiple
oxidation, aliphatic hydroxylation, and the loss of two carbon fragment from
the piperazine ring). The major circulating component in plasma was identified
as sildenafil accounting for 60 and 32% of the total radioactivity (AUC ratio)
for IV and oral administration, respectively. The corresponding major
circulating sildenafil metabolite was UK-103,320 (formed by piperazine N-
demethylation) accounting for 8.7% and 17% following IV and oral
administration, respectively. As mentioned in Section 15.6.4.4,in vitrostudies
indicate that sildenafil is metabolized to UK-103,320 by CYP2C9 and CYP3A4
(Hyland et al., 2001; Warrington et al., 2000).
15.7.3 Drug–Drug Interaction Potential
When projecting the drug–drug interaction potential of a particular drug, the
extent to which the drug is eliminated by the inhibited enzyme is key to
understanding the overall impact of the inhibition. Once the fraction
metabolized (% dose) for the major metabolic pathways of a compound have
been estimated (see Section 15.7.2) and the enzymes responsible for those
pathways have been identified and the contribution quantitated, the overall
fraction metabolized by a specific enzyme can be estimated (fm(enz)). Prior to the
availability of the radiolabeled human ADME study,fm(enz)can be projected as a
product of the predictions for overall fraction metabolized, fraction metabolized
via a specific enzyme system, and fraction metabolized by the specific enzyme. It
FIGURE 15.7 Example plasma radioactivitytime profile for radiolabeled ADME
studies.
502 REACTION PHENOTYPING