Edward J. Flynn, Ph.D.
Department of Pharmacology and Physiology
UMDNJ - New Jersey Medical School
Medical Sciences Building, I615/I606
185 S. Orange Avenue
Newark, NJ 07103
(973) 972-5451
eflynn@umdnj.edu
The Use of Macromolecules as an Approach to Therapeutic or Toxicologic Problems
The overall goal of the laboratory is to develop and define the properties of several
macromolecules (proteins or peptides) that have therapeutic potential. Traditionally low
molecular weight chemicals have been the mainstay of drug therapy and the focus of
pharmacological research. However, recombinant DNA technology has allowed
macromolecules to gain considerable ground as potential therapeutic agents. The
macromolecules that are being studied are of two main types, a family of chemical-specific
immunoglobulins and the protein hormone, erythropoietin (EPO).
The first group are a variety of chemical specific antibodies that are investigated because
they have the ability to manipulate chemicals in vivo. The antibodies were generated by
coupling the environmental carcinogen/teratogen, benzo(a)pyrene, to a protein which was
used to immunize rabbits. The serum from rabbits is utilized as a source of antibodies which
specifically bind benzo(a)pyrene with high affinity. The antibodies are administered to mice
and their ability to influence the behavior of subsequently administered benzo(a)pyrene is
assessed. The potential of immunoglobulin binding of teratogens to decrease their diffusion
into fetal tissue and thereby reduce the incidence of birth defects is being studied.
The second grouping of macromolecules being investigated include recombinant human
EPO, an anti-EPO antibody and an EPO binding protein. The disposition of EPO in mice has
been determined in the presence and absence of the binding protein. The binding protein
shortens the alpha and beta phase half-lives of intravenously administered EPO. At the same
time the ability of EPO to increase hematocrit levels is augmented. The mechanisms leading
to these observations are being investigated.
The approach to understanding the in vivo behavior of the macromolecules mentioned
above has been to combine data from whole animal studies following administration of the
macromolecule with computer pharmacokinetic modeling. This approach should allow a
detailed understanding of the fate of macromolecules and permit identification of novel targets
for drug development .


Pastino,G.M., Sultatos, L.G. and Flynn, E.J. Development and Application of a
Physiologically-Based Pharmacokinetic Model for Ethanol in the Mouse. Alcohol and
Alcoholism 31:365, 1996.
Pastino, G.M., Flynn, E.J. and Sultatos, L.G. Genetic polymorphisms in ethanol
metabolism: Issues and goals for physiologically based pharmacokinetic modeling.
Drug and Chem. Toxicol., 1999, in press.