Richard H. Ho, M.D.

Associate Professor

richard.ho@vanderbilt.edu

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Faculty Appointments
Associate Professor of Pediatrics
Education
M.S.C.I., Clinical Investigation, Vanderbilt University, Nashville, TennesseeM.D., Medicine, Vanderbilt University, Nashville, TennesseeB.S., Biology/History, Duke University, Durham, North Carolina
Office Address
397 PRB
Vanderbilt University Medical Center
2220 Pierce Ave.
Nashville, TN 37232
Research Description
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.
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Research Keywords
Drug Uptake Transporters and Chemotherapy Disposition
Publications
Frangoul H, Min E, Wang W, Chandrasekhar R, Calder C, Evans M, Manes B, Bruce K, Brown V, Ho R, Domm J. Incidence and risk factors for hypogammaglobulinemia in pediatric patients following allo-SCT. Bone Marrow Transplant [print-electronic]. 2013 Nov; 48(11): 1456-9. PMID: 23708706, PII: bmt201376, DOI: 10.1038/bmt.2013.76, ISSN: 1476-5365.

Vear SI, Stein CM, Ho RH. Warfarin pharmacogenomics in children. Pediatr Blood Cancer [print-electronic]. 2013 Sep; 60(9): 1402-7. PMID: 23682017, PMCID: PMC3786327, DOI: 10.1002/pbc.24592, ISSN: 1545-5017.

Lavoie Smith EM, Li L, Hutchinson RJ, Ho R, Burnette WB, Wells E, Bridges C, Renbarger J. Measuring vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia. Cancer Nurs. 2013 Sep; 36(5): E49-60. PMID: 23842524, PMCID: PMC3951303, DOI: 10.1097/NCC.0b013e318299ad23, ISSN: 1538-9804.

Minson KA, Prasad P, Vear S, Borinstein S, Ho R, Domm J, Frangoul H. T(17;19) in Children with Acute Lymphocytic Leukemia: A Report of 3 Cases and a Review of the Literature. Case Rep Hematol [print-electronic]. 2013; 2013: 563291. PMID: 23346431, PMCID: PMC3549381, DOI: 10.1155/2013/563291, ISSN: 2090-6560.

McManus MP, Wang L, Calder C, Manes B, Evans M, Bruce K, Ho RH, Domm J, Frangoul H. Comparison of pre-cryopreserved and post-thaw-and-wash-nucleated cell count on major outcomes following unrelated cord blood transplant in children. Pediatr Transplant [print-electronic]. 2012 Aug; 16(5): 438-42. PMID: 22533817, PMCID: PMC3391317, DOI: 10.1111/j.1399-3046.2012.01698.x, ISSN: 1399-3046.

DeGorter MK, Ho RH, Leake BF, Tirona RG, Kim RB. Interaction of three regiospecific amino acid residues is required for OATP1B1 gain of OATP1B3 substrate specificity. Mol. Pharm [print-electronic]. 2012 Apr 4/2/2012; 9(4): 986-95. PMID: 22352740, PMCID: PMC3319192, DOI: 10.1021/mp200629s, ISSN: 1543-8392.

Korhonen K, Lovvorn HN, Koyama T, Koehler E, Calder C, Manes B, Evans M, Bruce K, Ho RH, Domm J, Frangoul H. Incidence, risk factors, and outcome of pneumatosis intestinalis in pediatric stem cell transplant recipients. Pediatr Blood Cancer [print-electronic]. 2012 Apr; 58(4): 616-20. PMID: 21721114, DOI: 10.1002/pbc.23242, ISSN: 1545-5017.

Ho RH, Leake BF, Urquhart BL, Gregor JC, Dawson PA, Kim RB. Functional characterization of genetic variants in the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). J. Gastroenterol. Hepatol. 2011 Dec; 26(12): 1740-8. PMID: 21649730, PMCID: PMC3170668, DOI: 10.1111/j.1440-1746.2011.06805.x, ISSN: 1440-1746.

Esbenshade AJ, Ho RH, Shintani A, Zhao Z, Smith LA, Friedman DL. Dapsone-induced methemoglobinemia: a dose-related occurrence?. Cancer [print-electronic]. 2011 Aug 8/1/2011; 117(15): 3485-92. PMID: 21246536, PMCID: PMC3138875, DOI: 10.1002/cncr.25904, ISSN: 1097-0142.

Schwarz UI, Meyer zu Schwabedissen HE, Tirona RG, Suzuki A, Leake BF, Mokrab Y, Mizuguchi K, Ho RH, Kim RB. Identification of novel functional organic anion-transporting polypeptide 1B3 polymorphisms and assessment of substrate specificity. Pharmacogenet. Genomics. 2011 Mar; 21(3): 103-14. PMID: 21278621, PMCID: PMC3044558, DOI: 10.1097/FPC.0b013e328342f5b1, ISSN: 1744-6880.

Eckrich MJ, Yang E, Domm J, Ho R, Calder C, Manes B, Bleesing J, Frangoul H. A unique clinical presentation of X-linked lymphoproliferative syndrome with a novel mutation in SH2D1A and review of the literature. J. Pediatr. Hematol. Oncol. 2011 Jan; 33(1): e39-42. PMID: 20975587, DOI: 10.1097/MPH.0b013e3181e75747, ISSN: 1536-3678.

Ho RH, Leake BF, Kilkenny DM, Meyer Zu Schwabedissen HE, Glaeser H, Kroetz DL, Kim RB. Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability. Pharmacogenet. Genomics. 2010 Jan; 20(1): 45-57. PMID: 20010382, PMCID: PMC2883163, PII: 01213011-201001000-00006, DOI: 10.1097/FPC.0b013e3283349eb0, ISSN: 1744-6880.

Eckrich MJ, Domm J, Ho R, Whitlock JA, Frangoul H. Autologous stem cell transplant in a patient with Down syndrome and relapsed Hodgkin lymphoma. Pediatr Blood Cancer. 2009 Dec 12/15/2009; 53(7): 1327-8. PMID: 19760777, DOI: 10.1002/pbc.22182, ISSN: 1545-5017.

Frangoul H, Wang L, Harrell FE, Ho R, Domm J. Preengraftment syndrome after unrelated cord blood transplant is a strong predictor of acute and chronic graft-versus-host disease. Biol. Blood Marrow Transplant [print-electronic]. 2009 Nov; 15(11): 1485-8. PMID: 19822310, PII: S1083-8791(09)00319-X, DOI: 10.1016/j.bbmt.2009.07.001, ISSN: 1523-6536.

Piro CC, Crossno CL, Collier A, Ho R, Koyama T, Frangoul H. Initial vancomycin dosing in pediatric oncology and stem cell transplant patients. J. Pediatr. Hematol. Oncol. 2009 Jan; 31(1): 3-7. PMID: 19125078, PII: 00043426-200901000-00002, DOI: 10.1097/MPH.0b013e31818b3520, ISSN: 1536-3678.

Meyer zu Schwabedissen HE, Tirona RG, Yip CS, Ho RH, Kim RB. Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer. Cancer Res. 2008 Nov 11/15/2008; 68(22): 9338-47. PMID: 19010908, PMCID: PMC2597047, PII: 68/22/9338, DOI: 10.1158/0008-5472.CAN-08-0265, ISSN: 1538-7445.

Lavin VA, Hamid R, Patterson J, Alford C, Ho R, Yang E. Use of human androgen receptor gene analysis to aid the diagnosis of JMML in female noonan syndrome patients. Pediatr Blood Cancer. 2008 Aug; 51(2): 298-302. PMID: 18454468, DOI: 10.1002/pbc.21591, ISSN: 1545-5017.

Urquhart BL, Ware JA, Tirona RG, Ho RH, Leake BF, Schwarz UI, Zaher H, Palandra J, Gregor JC, Dresser GK, Kim RB. Breast cancer resistance protein (ABCG2) and drug disposition: intestinal expression, polymorphisms and sulfasalazine as an in vivo probe. Pharmacogenet. Genomics. 2008 May; 18(5): 439-48. PMID: 18408567, PMCID: PMC4043148, PII: 01213011-200805000-00008, DOI: 10.1097/FPC.0b013e3282f974dc, ISSN: 1744-6872.

Ho RH, Choi L, Lee W, Mayo G, Schwarz UI, Tirona RG, Bailey DG, Michael Stein C, Kim RB. Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants. Pharmacogenet. Genomics. 2007 Aug; 17(8): 647-56. PMID: 17622941, PMCID: PMC4063287, PII: 01213011-200708000-00009, DOI: 10.1097/FPC.0b013e3280ef698f, ISSN: 1744-6872.

Bagatell R, Gore L, Egorin MJ, Ho R, Heller G, Boucher N, Zuhowski EG, Whitlock JA, Hunger SP, Narendran A, Katzenstein HM, Arceci RJ, Boklan J, Herzog CE, Whitesell L, Ivy SP, Trippett TM. Phase I pharmacokinetic and pharmacodynamic study of 17-N-allylamino-17-demethoxygeldanamycin in pediatric patients with recurrent or refractory solid tumors: a pediatric oncology experimental therapeutics investigators consortium study. Clin. Cancer Res. 2007 Mar 3/15/2007; 13(6): 1783-8. PMID: 17363533, PII: 13/6/1783, DOI: 10.1158/1078-0432.CCR-06-1892, ISSN: 1078-0432.

Jones E, Koyama T, Ho RH, Kuttesch J, Shankar S, Whitlock JA, Cartwright J, Frangoul H. Safety and efficacy of a continuous infusion, patient-controlled antiemetic pump for children receiving emetogenic chemotherapy. Pediatr Blood Cancer. 2007 Mar; 48(3): 330-2. PMID: 16304666, DOI: 10.1002/pbc.20711, ISSN: 1545-5009.

McRae MP, Lowe CM, Tian X, Bourdet DL, Ho RH, Leake BF, Kim RB, Brouwer KL, Kashuba AD. Ritonavir, saquinavir, and efavirenz, but not nevirapine, inhibit bile acid transport in human and rat hepatocytes. J. Pharmacol. Exp. Ther [print-electronic]. 2006 Sep; 318(3): 1068-75. PMID: 16720753, PII: jpet.106.102657, DOI: 10.1124/jpet.106.102657, ISSN: 0022-3565.

Ho RH, Tirona RG, Leake BF, Glaeser H, Lee W, Lemke CJ, Wang Y, Kim RB. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology [print-electronic]. 2006 May; 130(6): 1793-806. PMID: 16697742, PII: S0016-5085(06)00390-8, DOI: 10.1053/j.gastro.2006.02.034, ISSN: 0016-5085.

Ho RH, Kim RB. Transporters and drug therapy: implications for drug disposition and disease. Clin. Pharmacol. Ther. 2005 Sep; 78(3): 260-77. PMID: 16153397, PII: S0009-9236(05)00225-0, DOI: 10.1016/j.clpt.2005.05.011, ISSN: 0009-9236.

Calder C, Hays SR, Manes B, Lavin VA, Ho RH, Frangoul H. Successful bone marrow harvest during pregnancy. Bone Marrow Transplant. 2005 Mar; 35(6): 631-2. PMID: 15756288, PII: 1704844, DOI: 10.1038/sj.bmt.1704844, ISSN: 0268-3369.

Ho RH, Johnson J, Dev VG, Whitlock JA. A novel t(2;20)(q35;p12) in embryonal rhabdomyosarcoma. Cancer Genet. Cytogenet. 2004 May; 151(1): 73-7. PMID: 15120913, PII: S016546080300390X, DOI: 10.1016/j.cancergencyto.2003.08.023, ISSN: 0165-4608.

Ho RH, Leake BF, Roberts RL, Lee W, Kim RB. Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition. J. Biol. Chem [print-electronic]. 2004 Feb 2/20/2004; 279(8): 7213-22. PMID: 14660639, PII: M305782200, DOI: 10.1074/jbc.M305782200, ISSN: 0021-9258.