Pharmacokinetic (PK) drug-drug interactions (DDIs) give rise to adverse events and/or reduced efficacy. Comprehensive, systematic
and mechanistic approaches have been applied in the evaluation, propagation and management of the interaction potential of a
new drug during its development and clinical use. However, the role of drug metabolite(s) in DDIs was not extensively investigated. Recently,
regulatory bodies have proposed that metabolites at ≥25% of the parent drug’s area under the time-concentration curve (AUC)
and/or >10% of the total drug-related exposure should be investigated in vitro for DDI potential. This review aimed to identify the drugs
and their metabolites meeting the official guidance’s criteria for DDI studies, and to assess whether the eligible drugs caused significant
clinical PK DDIs and furthermore whether the metabolites contributed to the observed PK DDIs. Eighty seven drugs were eligible and
nearly 45% (39/87) drugs were not reported with clinical PK DDIs. About 78% (68/87) drugs demonstrated inhibitory and/or inducible
effects on drug-metabolizing enzymes and/or drug transporters; while the remaining 19 (22%) parent drugs showed no such effects. For 8
drugs (~9%), their metabolites were able to inhibit and/or induce the drug-metabolizing enzymes and drug transporters. Three drugmetabolite
pairs were found to be the perpetrators of the complex PK DDIs. Our retrospective analysis suggested that the PK DDI risks
caused by metabolites alone might not be high, which is somewhat different from the conclusions from some other studies on this topic.
However, circulating drugs often work as perpetrators of PK DDIs suggesting a need for more efforts to characterize the roles of their
metabolites. Our study should be of value in stimulating discussions among the scientific community on this important topic.
Keywords: Human drug metabolites, inhibitory roles, official investigation guidance, pharmacokinetic drug-drug interactions.
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