In vitro approaches which reliably predict in vivo human drug metabolite profiles are highly desired as a means to streamline drug development timelines and substantially reduce development costs. Major metabolites of many compounds can be predicted using traditional in vitro systems such as liver microsomes. The rates of success, however, are typically in the range of 50%. Thus, there is considerable room for improving in vitro systems for predicting human metabolite profiles. This case study demonstrates the increased success of Hepregen’s HepatoPac system in identifying primary and secondary circulating and excretory metabolites when compared to liver microsomes, S-9 fractions and primary human hepatocyte suspensions for a series of 27 compounds with known in vivo human metabolite profiles.