Our research program focuses on the molecular mechanisms by
which drug transporters contribute to overall chemotherapy
disposition and interindividual response to drug therapy in cancer
therapy. Drug transport proteins have important roles in modulating
the absorption, distribution, and excretion of many drugs and drug
metabolites as well as endogenous substances. They tend to be
highly expressed in tissues of importance to drug disposition,
including the liver, intestine, kidney and at the blood:brain
barrier. To this extent, a major focus in my lab centers on the
contribution of specific drug uptake transporters, in particular
the organic anion transporting polypeptide (OATP) family and bile
acid uptake transporters, to the disposition of pediatric
chemotherapeutic agents. In addition, another area of major focus
is cancer pharmacogenetics, the study of the role of inheritance in
the individual variation in chemotherapy response. Projects are
primarily laboratory based with translational promise and rely on
background knowledge in the fields of molecular biology and
clinical pharmacology. We utilize a number of in vitro techniques
to study these transporter proteins, including vaccinia-based
expression systems for functional transport studies, drug
screening, and drug inhibition studies, protein expression studies
utilizing western analysis, immunohistochemistry and
immunofluorescent confocal microscopy, and generation of polarized
stable cell lines for directional transport studies and
comprehensive kinetic analysis. We have also integrated animal
models utilizing recently generated knockout mice for various
transporter genes into our research program for in vitro:in vivo
correlative data in our drug disposition studies.
Moreover, our research has important implications for drug
discovery and experimental therapeutics. ADME (absorption,
distribution, metabolism and excretion) deficiency is one of the
major causes of failure during drug development. In vitro ADME
screening of potential lead compounds and drug candidates in the
early discovery phase has been employed as a more cost-effective
approach to identify compounds that have unfavorable drug-like
characteristics. Many compounds with promising pharmacological
characteristics never become drugs because they have poor
solubility, quickly degrade in biological fluids and tissues or
rapidly metabolized in the liver. Utilizing our in vitro screening
transport and detailed studies of kinetic analysis, we are able to
identify potential drug compounds as substrates for a complement of
drug uptake and efflux transporters, which may have important
implications not only for drug disposition in vivo, but also for
drug toxicity, efficacy and tissue targeting. Furthermore, as many
of the transporters we study are known to be polymorphic, we have
the ability to assess transporter polymorphisms for differential
transport of drugs and/or drug metabolites, which may have
significant consequences for determining the interindividual
response to anticancer agents.
- Richard Ho
Owner- Brenda Leake
Lab Manager- Hannah Lee
Research Instructor
2220 Pierce Avenue
338 Preston Research Bldg.
Nashville, TN 37232
USA
615-936-7171 (p)
615-936-1767 (f)
Richard Ho
615-936-2802 (p)
615-936-1767 (f)
MeSH terms are retrieved from PubMed records. Learn more.
Key: MeSH Term Keyword
Adult Agammaglobulinemia ATP Binding Cassette Transporter, Subfamily B, Member 1 ATP Binding Cassette Transporter, Subfamily G, Member 2 Blacks Bone Marrow Cancer Research Chronic Disease Cohort Studies Drug transporters Etoposide Hispanic or Latino Length of Stay Lorazepam Maximum Tolerated Dose Metabolic Clearance Rate Mixed Function Oxygenases Peptide Fragments Pharmacogenetics Pharmacokinetics Pharmacology Protein Conformation Vinblastine Warfarin Young Adult