Demographic and genomic factors contributing to individual variability in zolpidem metabolism in vitro.
Abstract: Zolpidem is
the most commonly prescribed hypnotic drug in a number of Western countries. However,
reports of severe next morning drowsiness with zolpidem use, particularly among
women, has caused concern. In 2013, the FDA issued a warning regarding such effects and
recommended that activities requiring full mental acuity should be avoided during the
morning following a zolpidem dos... read moree. Such effects are likely attributable to variability
in the rate of zolpidem metabolism among individuals. This exploratory investigation
utilized an in vitro human liver microsomal model and single nucleotide polymorphism
genotyping to evaluate the extent to which various demographic and genetic factors
contribute to the individual variability in the rate of zolpidem metabolism. We found
that age and sex were the primary demographic determinants of reduced in vitro zolpidem
metabolism. A number of polymorphisms in CYP-encoding genes (rs2242480, rs776746,
rs762551, rs2470890, and rs35694136) that appeared to increase the rate of in vitro
zolpidem metabolism were identified, as well as 2 (rs4244285 and rs12248560) that
appeared to decrease the rate of in vitro zolpidem metabolism. A high coincidence of
expression of 2 CYP3A mutations (rs2242480 and rs776746) was observed and may represent
a novel "rapid metabolizer" CYP3A haplotype particularly common in populations of
African descent. These findings are preliminary and require in vivo replication before
metabolic relevance can be ascribed to the aforementioned demographic and genomic
Thesis (M.S.)--Tufts University, 2016.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisor: David Greenblatt.
Committee: Martin Beinborn.
Keywords: Pharmacology, Genetics, and Medicine.read less