How do you catch a drug-safety problem before it trips you up in human trials? Try making a mouse with a human liver – or one close enough to human to predict what the drug you’re testing will do in a person.
A team led by Stanford pharmacogenomic expert Gary Peltz, MD, PhD, in a study just published in the Journal of Pharmacology and Experimental Therapeutics, designed and used just such mice to show precisely how a compound showing promise for fighting HCV (the virus responsible for hepatitis C) would be metabolized in people. Not only that, but these ‘humanized’ mice accurately predicted how the compound would interact with another, already approved HCV drug in human subjects. (With more than 30 percent of all people over age 57 taking five or more prescription drugs at any given time, drug-drug interactions are a serious concern.)
The liver is the body’s chemistry set. In this hardworking organ, batteries of enzymes (molecular machines that do most of the body’s chores) operate in careful sequences like workstations of an assembly line. Together, they manufacture myriad substances and modify existing ones. They also constitute the body’s front-lne detox unit, metabolizing potentially poisonous ingested substances. That includes drugs we consume for medical purposes.
Metabolites – the products of metabolism – can themselves be bioactive, for better or for worse. “It’s often not the drug itself, but one of its metabolites, that is responsible for a drug-induced toxicity,” Peltz told me when I interviewed him for the release I wrote on the new study. So drug developers rigorously test their drugs in animals, typically starting with mice, before moving into clinical trials.
But mice metabolize things differently from humans, because our livers are different. That can make for nasty surprises. All too often, drugs showing tremendous promise in preclinical animal assessments fail in human trials due to unforeseen safety problems, said Peltz. Another big problem is those unanticipated interactions between a new drug a person takes and any other drugs that person may already been taking.
The drug tested in the study, clemizole, is an old antihistamine widely prescribed in the 1950s and 1960s but left on the shelf when newer drugs came along. Stanford HCV authority Jeff Glenn, MD, PhD, has resurrected clemizole after observing that it impedes the virus’s replication. The new study advances clemizole’s prospects for development, because what the drug appears to do in human liver tissue is just what the doctor ordered.