Which Metabolites Circulate?

Abstract

Characterization of the circulating metabolites for a new chemical entity in humans is essential for safety assessment, an understanding of their contributions to pharmacologic activities, and their potential involvement in drug-drug interactions. This review examines the abundance of metabolites relative to the total parent drug [metabolite-to-parent (M/P) ratio] from 125 drugs in relation to their structural and physicochemical characteristics, lipoidal permeability, protein binding, and fractional formation from parent (f m ). Our analysis suggests that f m is the major determinant of total drug M/P ratio for amine, alcohol, N-and S-oxide, and carboxylic acid metabolites. Passage from the hepatocyte to systemic circulation does not appear to be limiting owing to the vast majority of metabolites formed being relatively lipid permeable. In some cases, active transport plays an important role in this process (e.g., carboxylic acid metabolites). Differences in total parent drug clearance and metabolite clearance are attenuated by the reduction in lipophilicity introduced by the metabolic step and resultant compensatory changes in unbound clearance and protein binding. A small subclass of these drugs (e.g., terfenadine) is unintentional prodrugs with very high parent drug clearance, resulting in very high M/P ratios. In contrast, arenol metabolites show a more complex relationship with f m due largely to the new metabolic routes (conjugation) available to the metabolite compared with the parent drug molecule. For these metabolites, a more thorough understanding of the elimination clearance of the metabolite is critical to discern the likelihood of whether the phenol will constitute a major circulating metabolite.

Pharmacokinetics, Metabolism, and Excretion of [14C]Axitinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Humans

“…This suggests that the conversion of axitinib to the N-glucuronide is a minor clearance mechanism even though it is a major metabolite in plasma. The factors that cause the apparent disconnect between metabolite abundance in plasma and clearance are known and have been well described by others (Lutz et al, 2010;Loi et al, 2013). Finally, taken together, these and other data suggest that liver is the primary organ involved in the clearance of axitinib from the body.…”

A Pharmacokinetic Modeling Approach to Predict the Contribution of Active Metabolites to Human Efficacious Dose

“…Nonetheless, regulatory guidelines exist for the characterization of human metabolites according to whether they are deemed to have been adequately tested during preclinical toxicology [Food and Drug Administration, 2012 (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM079266.pdf); International Conference on Harmonization, 2012 (http://www.ich.org/products/guidelines/multidisciplinary/article/ multidisciplinary-guidelines.html)]. Partially as a consequence of these guidelines, there has been much research into the prediction, detection, and quantification of human circulating metabolites (Anderson et al, 2009;Dalvie et al, 2009;Leclercq et al, 2009;Pelkonen et al, 2009;Lutz et al, 2010;Luffer-Atlas, 2012;Loi et al, 2013). The theoretical basis for predicting metabolite exposure has been discussed by Lutz et al (2010).…”

A decade of drug metabolite safety testing: industry and regulatory shared learning

“…Since publication of the metabolite safety testing guidance, an increasing number of sponsor submissions have provided some assessment of drug metabolism in the first-in-human study protocol, consistent with prediction of potential major human metabolites based on in vitro metabolism. Unfortunately, in vitro metabolic profiles from liver microsomes and/or hepatocyte incubations can be poor predictors of in vivo circulating major human metabolites [11,12]. Sometimes the exact structure of seemingly major human metabolite(s) cannot be ascertained or a metabolite standard cannot be easily synthesized, so nontraditional approaches to establish metabolite coverage are needed.…”