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.

Publications

Featured publications

  1. The impact of age and CYP2C9 and VKORC1 variants on stable warfarin dose in the paediatric population. Vear SI, Ayers GD, Van Driest SL, Sidonio RF, Stein CM, Ho RH (2014) Br J Haematol 165(6): 832-5
    › Primary publication · 24601977 (PubMed) · PMC4043918 (PubMed Central)
  2. Measuring vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia. Lavoie Smith EM, Li L, Hutchinson RJ, Ho R, Burnette WB, Wells E, Bridges C, Renbarger J (2013) Cancer Nurs 36(5): E49-60
    › Primary publication · 23842524 (PubMed) · PMC3951303 (PubMed Central)
  3. Warfarin pharmacogenomics in children. Vear SI, Stein CM, Ho RH (2013) Pediatr Blood Cancer 60(9): 1402-7
    › Primary publication · 23682017 (PubMed) · PMC3786327 (PubMed Central)
  4. Interaction of three regiospecific amino acid residues is required for OATP1B1 gain of OATP1B3 substrate specificity. DeGorter MK, Ho RH, Leake BF, Tirona RG, Kim RB (2012) Mol Pharm 9(4): 986-95
    › Primary publication · 22352740 (PubMed) · PMC3319192 (PubMed Central)
  5. Functional characterization of genetic variants in the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). Ho RH, Leake BF, Urquhart BL, Gregor JC, Dawson PA, Kim RB (2011) J Gastroenterol Hepatol 26(12): 1740-8
    › Primary publication · 21649730 (PubMed) · PMC3170668 (PubMed Central)
  6. Identification of novel functional organic anion-transporting polypeptide 1B3 polymorphisms and assessment of substrate specificity. Schwarz UI, Meyer zu Schwabedissen HE, Tirona RG, Suzuki A, Leake BF, Mokrab Y, Mizuguchi K, Ho RH, Kim RB (2011) Pharmacogenet Genomics 21(3): 103-14
    › Primary publication · 21278621 (PubMed) · PMC3044558 (PubMed Central)
  7. Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability. Ho RH, Leake BF, Kilkenny DM, Meyer Zu Schwabedissen HE, Glaeser H, Kroetz DL, Kim RB (2010) Pharmacogenet Genomics 20(1): 45-57
    › Primary publication · 20010382 (PubMed) · PMC2883163 (PubMed Central)
  8. Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer. Meyer zu Schwabedissen HE, Tirona RG, Yip CS, Ho RH, Kim RB (2008) Cancer Res 68(22): 9338-47
    › Primary publication · 19010908 (PubMed) · PMC2597047 (PubMed Central)
  9. Breast cancer resistance protein (ABCG2) and drug disposition: intestinal expression, polymorphisms and sulfasalazine as an in vivo probe. Urquhart BL, Ware JA, Tirona RG, Ho RH, Leake BF, Schwarz UI, Zaher H, Palandra J, Gregor JC, Dresser GK, Kim RB (2008) Pharmacogenet Genomics 18(5): 439-48
    › Primary publication · 18408567 (PubMed) · PMC4043148 (PubMed Central)
  10. Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants. Ho RH, Choi L, Lee W, Mayo G, Schwarz UI, Tirona RG, Bailey DG, Stein CM, Kim RB (2007) Pharmacogenet Genomics 17(8): 647-56
    › Primary publication · 17622941 (PubMed) · PMC4063287 (PubMed Central)

Community Leaders

Contact Information

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)
Email

Keywords & MeSH Terms

MeSH terms are retrieved from PubMed records. Learn more.

Key: MeSH Term Keyword

Agammaglobulinemia Animals Antineoplastic Agents, Phytogenic Bone Marrow Cancer Research Chromatin Immunoprecipitation Chronic Disease Cohort Studies Cryopreservation Drug transporters Etoposide Genotype HLA Antigens Length of Stay Metabolic Clearance Rate Mutation, Missense Pharmacogenetics Pharmacokinetics Pharmacology Retrospective Studies Self Administration Species Specificity Vinblastine Warfarin Young Adult