%0 Journal Article %A Chandra Prakash %A Zhaoyang Li %A Cesare Orlandi %A Lewis Klunk %T Assessment of Exposure of Metabolites in Preclinical Species and Humans at Steady State from the Single-Dose Radiolabeled Absorption, Distribution, Metabolism, and Excretion Studies: A Case Study %D 2012 %R 10.1124/dmd.112.044933 %J Drug Metabolism and Disposition %P 1308-1320 %V 40 %N 7 %X The exposure of a drug candidate and its metabolites in humans and preclinical species during drug development needs to be determined to ensure that the safety of drug-related components in humans is adequately assessed in the standard toxicology studies. The in vivo radiolabeled studies in preclinical species and human volunteers provide the total fate of the drug-derived radioactivity including the relative abundance of metabolites. Here, we describe how the single-dose radiolabeled human studies could provide the exposure of circulating metabolites at steady state using a case study of an extensively metabolized drug, lixivaptan. After an oral dose of [14C]lixivaptan to humans, a total of nine metabolites were detected in the systemic circulation; eight of them exceeded 10% of the parent exposure (2–41% of total radioactivity). The plasma samples were profiled for all subjects at each time point by high-performance liquid chromatography, and metabolites were quantified using a radioactive detector. On the basis of single-dose area under the concentration-time curve (AUC) values, exposure of six human metabolites was greater at least in one preclinical species used in toxicology evaluation. On the basis of the t1/2 of lixivaptan and two major metabolites from a single dose in humans, their AUC and Cmax values were simulated at the steady state. The simulated exposure (Cmax and AUC) values of parent drug and the two most abundant metabolites were similar to those from a 7-day clinical study obtained using a validated liquid chromatography-mass spectrometry assay, suggesting that a well designed single-dose radiolabeled human study can help in addressing the metabolites in safety testing-related issues. %U https://dmd.aspetjournals.org/content/dmd/40/7/1308.full.pdf