THE PREDICTIVE NATURE OF
SCREENING USING A HUMAN
HEPATOCYTE CELL LINE
Norman L. Sussman, M.D.1, Monika Waltershied, M.S.1,
Terolyn Butler, M.S.1, James J. Cali, Ph.D.2, Terry Riss, Ph.D.2,
and James H. Kelly, Ph.D.1, Amphioxus Cell Technologies1 and
Drug discovery has become an industrialized process
in which vast libraries of compounds are screened for
activity against a chosen target. The wealth of active
compounds that emerge from these primary screens
has created a bottleneck in drug development. First-
round hits do not often meet the safety and efficacy
criteria required for human therapeutics, so
sequential rounds of optimization are required before
a product can be administered to humans.
Optimization requires assays that test Absorption,
Distribution, Metabolism, Elimination, and Toxicity
(ADME/Tox). In this paper we demonstrate the utility
of high-throughput testing in a human liver cell line.
If the technologies and reagents presented in this
article had been available earlier, ADME/Tox screening
could have prevented deaths and costly drug recalls by
two major pharmaceutical companies.
Historically, antihistamines have been a very safe class of
drugs (1). However, two drugs, terfenadine (Seldane®)
and astemizole (Hismanal®) were withdrawn from the
market because of serious side effects. Both drugs were
found to cause life-threatening cardiac arrhythmias when
given in high doses or co-administered with certain
antibiotics like erythromycin and ketoconazole (2). This
surprising toxicity provides an excellent case study in light
of the number of safe antihistamines currently on the
market and the growing interest among pharmaceutical
scientists in early ADME/Tox screening.
The presumption that chemical libraries contain
compounds with a spectrum of positive and negative
effects forms the foundation of ADME/Tox screening.
Beneficial features of a drug candidate include high
specificity, low toxicity, good oral absorption and half-life,