Principal Investigator

Teaching Summary:

               My goal as a teacher and mentor is to not only share my knowledge with the students and trainees, but also to inspire them to enjoy learning, and to share their joy of learning with others.

Research Summary:

         My research focuses on post-translational regulation of hepatic transport proteins organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 as well as the implication of such regulation in clinical significant drug-drug interactions. My research utilize multidisciplinary approaches, including gene-knockout models, contemporary cell and molecular biology techniques, and pharmacokinetic modeling and simulation, to advance the safe usage of drugs.

Education and Training: 

• Postdoctoral Training in hepatic drug transport, UNC Eshelman School of Pharmacy, the University of North Carolina at Chapel Hill (2008)

• Postdoctoral Training in Tumor Virology, Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill (2007)

• Ph.D. in Developmental Biology, Joint PhD program in Peking Union Medical College and Shandong University, China (2001)

Employment:

• Associate Professor, Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, College of Pharmacy (2020–present)

• Member of Stephenson Cancer Center, University of Oklahoma Health Sciences Center, College of Pharmacy (2012–present)

• Assistant Professor, Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, College of Pharmacy (2012–2020)

• Research Assistant Professor, UNC Eshelman School of Pharmacy, the University of North Carolina at Chapel Hill (2008-2012)

Awards and Honors:

• Educators for Excellence of OUHSC (2022)

• OUHSC Provost’s Teaching Award-Early Career Faculty (2021)

• Kwang-Hua Scholarship (1996)

• Exempted from enrollment test for prospective graduate students through Outstanding College Student of China status (1995)

• Graduation with Distinction (1995)

• Outstanding College Student of China (among 50 total awards nationwide) (1993)

• The First-Grade college scholarship in successive years from 1991 to 1995

Professional membership:

International Transporter Consortium (ITC)

American Society for Pharmacology and Experimental Therapeutics (ASPET)

American Association of Pharmaceutical Scientists (AAPS)

International Society of Study of Xenobiotics (ISSX)

American Association of Colleges of Pharmacy (AACP)

Didactic Teaching:

Professional PharmD Courses:

         PHAR 7523 Clinical Toxicology

         PHAR 7133 Principle of Drug Action I

         PHAR 7862 Pharmaceutical Care VI

PHAR 7834 Pharmacokinetics 

Graduate Courses:

         PHSC 5212  Drug Metabolism and Transporters

         PHSC 5643 Pharmacokinetics

         PHSC 5653 Advanced Pharmacokinetics & Pharmacodynamics

PHSC 5561  General Principles of Pharmacology

PHSC 5581  General Principles of Toxicology

BMSC 5221  Interdisciplinary Journal Club on drug transporters 

Grants and Sponsored Research:

• GM146956-01 NIH/NIGMS R01

Title: Regulation of OATP1B1 and OATP1B3 by lysine acetylation and lysine deacetylase inhibitors

Funding period: Sept 2022-June 2026

Total: $1,160,000

Role: Principal Investigator

• Oklahoma Presbyterian Health Foundation Bridge Award

Title: Regulation of OATP1B1 and OATP1B3 by lysine acetylation and lysine deacetylase inhibitors

Funding period: July 2022-June 2023

Total: $75,000

Role: Principal Investigator

• College of Pharmacy OUHSC seed grant 

Title: Lysine Acetylation: A novel mechanism governing organic anion transporting polypeptides OATP1B1- and OATP1B3-mediated transport

Funding period: August 2021-July 2022        

Total: $10,000                                      

Role: Principal Investigator

• Oklahoma Presbyterian Health Foundation Seed Grant

Title: Elucidating novel mechanism underlying OATP1B1/1B3-mediated drug-drug interactions

Funding period: July 2019 – December 2020

Total: $50,000

Role: Principal Investigator

• GM094268 NIH/NIGMS R01

 Title: Function and regulation of OATP1B1 and OATP1B3 (R01)

NIH-National Institute of General Medical Sciences (NIGMS)

Funding period: September 2011-August 2018

Total: $1,497,175

Role: Principal Investigator

• GM094268 NIH/NIGMS R01 Administrative Supplemental Award

FV 10i-LIV Confocal Imaging System

Funding period: 9/10/2015-8/31/2018

Total: $115,000

Role: Principal Investigator

Contributions to Science:

1. Contribution of breast cancer resistance protein (Bcrp) to biliary excretion of xenobiotics. Hepatic transport proteins are important for drug disposition. Understanding the role of each individual transport protein in overall hepatic disposition and hepatotoxicities is important for personalized therapy. However, obtaining such information is challenging, due to the overlapping substrate specificity of the transporters. My early work as a postdoctoral fellow and Research Assistant Professor at Eshelman School of Pharmacy of University of North Carolina at Chapel Hill contributed to the field by developing a novel loss-of-function model in sandwich-cultured rat hepatocytes with specific knockdown of transporter breast cancer resistance protein (Bcrp) and multidrug resistance protein (Mrp) 2. These models have been utilized to characterize the contribution of individual transport proteins Bcrp and Mrp2 to overall hepatic biliary excretion of several drugs, including clinical contrast imaging agent 99mTechnetium-Sestamibi, antibiotic nitrofurantoin, and lipid-lowering statins. I also discovered the reduced protein levels and transport function of Bcrp in Mrp2-deficient TR- rats. This finding highlighted the important role of Bcrp in the biliary excretion of many drugs/metabolites, which may have been previously underestimated because of the unrecognized reduced Bcrp function in TR- rats. The following publications demonstrate my expertise and experience in studying hepatic drug disposition in sandwich-cultured hepatocytes, isolated perfused liver, and the determination of hepatocellular drug concentration using B-Clear technology®.

a. Yue W, Abe K, Brouwer KL. Knocking down breast cancer resistance protein (Bcrp) by adenoviral vector-mediated RNA interference (RNAi) in sandwich-cultured rat hepatocytes: a novel tool to assess the contribution of Bcrp to drug biliary excretion. Mol Pharm. 2009, 6:134-43. 

b. Yue, W., Lee, J., Abe, K., Brouwer, K. L. R., Decreased hepatic breast cancer resistance protein expression and function in multidrug resistance-associated protein 2-deficient TR- rats. Drug Metab Dispos. 2011, 39: 441-47.

c. Abe K, Bridges AS, Yue W, Brouwer KL. In vitro biliary clearance of angiotensin II receptor blockers and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in sandwich-cultured rat hepatocytes: comparison with in vivo biliary clearance. J Pharmacol Exp Ther. 2008, 326:983-90. 

d.  Swift B, Yue W, Brouwer KL. Evaluation of (99m)technetium-mebrofenin and (99m)technetium-sestamibi as specific probes for hepatic transport protein function in rat and human hepatocytes. Pharm Res. 2010, 27:1987-98. 

2. Regulation of OATP1B1 and OATP1B3 transport function. Lack of understanding of the mechanism(s) underlying functional regulation of hepatic transport proteins OATP1B1 and OATP1B3 limits DDI prediction. The current studies on impaired OATP1B1- and OATP1B3-mediated transport by perpetrator drugs are focused primarily on competitive inhibition. My laboratory for the first time reported that OATP1B3 is a phosphorylated protein in primary human hepatocytes, and reported that increased phosphorylation of OATP1B3 is associated with rapid reduction of transporter function after protein kinase C (PKC) activation. My laboratory is also the first to report that OATP1B1 and OATP1B3 are ubiquitinated proteins. However, the lysosome, but not the proteasome, is the major degradation pathway of OATP1B1 and OATP1B3. Consistent with these in vitro findings, pharmacoepidemiology studies using the US FDA Adverse Event Reporting System suggest that concurrent use of statins with the lysosome inhibitor chloroquine, but not proteasome inhibitor bortezomib, increases myopathy risk. For nearly two decades, it has been widely believed that reduced plasma membrane level is the underlying mechanism of the reduced transport function of the V174A-OATP1B1 variant, a clinically important OATP1B1 polymorphism with reduced transport function and predicting statin-induced myopathy. However, the initial finding of this study could not be reproduced by three laboratories, including my laboratory. Our findings revealed that the OATP1B1 is phosphorylated protein and that the V174A-OATP1B1 variant has similar plasma membrane localization to the wild-type OATP1B1 in vivo in genotyped human liver tissue. Interestingly, the V174A-OATP1B1 has significantly increased phosphorylation compared with the wild-type OATP1B1. This work was recognized as the cover image in 2019 Pharm. Res. and in the 2022 White paper on Behalf of the International Transporter Consortium. These findings highlight the importance of our ongoing research identifying post-translational modification(s) that is important in regulating OATP1B1 and OATP1B3 transport function. 

a. Powell J, Farasyn T, Köck K, Meng X, Pahwa S, Brouwer KL, Yue W. Novel mechanism of impaired function of organic anion-transporting polypeptide 1B3 in human hepatocytes: post-translational regulation of OATP1B3 by protein kinase C activation. Drug Metab Dispos. 2014, 42:1964-70. 

b. Alam K, Pahwa S, Wang X, Zhang P, Ding K, Abuznait AH, Li L, Yue W. Downregulation of organic anion transporting polypeptide (OATP) 1B1 transport function by lysosomotropic drug chloroquine: implication in OATP-mediated drug-drug interactions. Mol Pharm. 2016, 13:839-51. 

c. Alam, K., Farasyn, T., Crowe, A., Ding, K., and Yue, W. Treatment with proteasome inhibitor bortezomib decreases organic anion transporting polypeptide (OATP) 1B3-mediated transport in a substrate-dependent manner. Public Library of Science ONE. 2017, 12:11 e0186924

d.    Crowe A, Zheng W, Miller J, Pahwa S, Alam K, Fung K, Rubin E, Yin F, Ding K, Yue W. Characterization of plasma membrane localization and phosphorylation status of organic anion transporting polypeptide (OATP) 1B1 c.521 T>C polymorphism. Pharm Res. 2019, 36: 101 (Cover image in 2019 July issue)

e.    Brouwer, K., Evers, R., Hayden, E., Hu, S., Li, C., Meyer zu Schwabedissen, H., Neuhoff, S., Oswald, S., Piquette-Miller, M., Saran, C., Sjostedt, N., Sprowl, J., Stahl, S., and Yue, W., Regulation of Drug Transport Proteins - From Mechanisms to Clinical Impact; A White Paper on Behalf of the ITC, Clinical Pharmacology & Therapeutics, 2022, 112: 461-84

3. Implement time-dependent OATP1B1/3-inhibition in prediction of OATP1B1- and OATP1B3-mediated DDIs. Assessing in vivo inhibition constant (Ki) values of inhibitors against OATP1B1/3 from in vitro experiments is a challenging issue in drug development. It is particularly difficult for drugs with high protein binding and poor aqueous solubility. My laboratory is one of the leading laboratories to report that in vitro preincubation with inhibitors, including cyclosporine A (CsA), rifampicin, tyrosine kinase inhibitor dasatinib, and mTOR kinase inhibitors everolimus and sirolimus, yielded reduce IC50 values against OATP1B1/3, and the reduced IC50 values for rifampicin, a prototypical OATP1B1 and OATP1B3 inhibitor, were similar to the estimated in vivo Ki value. Such time-dependent inhibition of OATP1B1/3 from my laboratory and three others were cited by the US FDA to support the newly implemented final guidance to industry recommending to add a pre-incubation step as part of assay validation when determining IC50 values for an investigational drug. My laboratory is the first to report that pre-incubation with OATP1B inhibitors potentiates inhibitory effects in physiologically relevant primary human hepatocytes, supporting the rationale of the current US FDA guidance of including an inhibitor-preincubation step when assessing OATP-mediated DDIs in vitro. To conquer the difficulty of working with a compound with high protein binding and low aqueous solubility, we utilized a total IC50 approach to determine the inhibitory effect of vemurafenib, a drug with high protein binding and low aqueous solubility, on OATP1B1 and OATP1B3. Using physiologically based pharmacokinetic (PBPK) model, we predict that vemurafenib has the potential to have DDIs with statins. Such DDI potential would have been overlooked using the conventional method of IC50 determination in protein-free buffer. The below publications in my lab contribute to prediction of OATP1B1- and OATP1B3-mediated DDIs.

a.    Pahwa S, Alam K, Crowe A, Farasyn T, Neuhoff S, Hatley O, Ding K and Yue W. Pretreatment with rifampicin and tyrosine kinase inhibitor dasatinib potentiates the inhibitory effects toward OATP1B1- and OATP1B3-mediated transport. J Pharm Sci. 2017, 106(8):2123-35. 

b.    Kayesh, R., Farasyn, T., Crowe, A., Liu, Q., Pahwa, S., Alam, K., Neuhoff, S., Hatley, O., Ding, K. and Yue, W., Assessing OATP1B1- and OATP1B3-mediated drug-drug interaction potential of vemurafenib using R-value and physiologically based pharmacokinetic models J Pharm Sci. 2021, 110: 314.

c. Farasyn, T., Crowe, A., Hatley, O., Neuhoff, S., Alam, K., Kanyod, J., Lamd, T., Ding, K. and Yue, W., Assessing organic anion transporting polypeptide (OATP) 1B1- and 1B3-mediated drug-drug interaction of mammalian target of rapamycin (mTOR) inhibitors everolimus and sirolimus. J Pharm Sci. 2019, 108: 3443-3456.

d. Farasyn, T., Pahwa, S., Xu, C., and Yue, W., Pre-incubation with OATP1B1 and OATP1B3 inhibitors potentiates inhibitory effects in physiologically relevant sandwich-cultured primary human hepatocytes. European Journal of Pharmaceutical Sciences, 2021, 165: 105951.