About

Kim Brouwer is the William R. Kenan, Jr. Distinguished Professor and Associate Dean at the University of North Carolina Eshelman School of Medicine. His research involves both non-clinical and clinical studies focused on hepatobiliary xenobiotic disposition, including mechanisms of hepatic uptake, translocation, and biliary excretion. He investigates mechanisms of transporter-mediated drug-induced liver injury and develops strategies such as in vitro model systems, pharmacokinetic modeling, and simulation to predict the impact of hepatic transporter-mediated alterations caused by disease, genetics, and pharmacologic or toxicologic interactions.

Research topics

• Biology
• Pharmacology
• Bioinformatics
• Computational biology
• Medicine
• Biochemistry
• Cell biology
• Internal medicine
• Materials science
• Nanotechnology
• Genetics
• Endocrinology
• Gastroenterology
• Psychology

Selected publications

• Comparison of Metformin <scp>PBPK</scp> Models Incorporating Placental Transfer to Predict Fetal and Maternal Exposure

  CPT Pharmacometrics & Systems Pharmacology · 2025-11-25

  articleOpen access

  ABSTRACT Physiologically based pharmacokinetic (PBPK) modeling of placental drug transfer is an evolving tool for predicting fetal drug exposure. In this study, a pregnancy‐specific metformin PBPK model was developed, and the following four approaches were evaluated to predict metformin placental transfer: (1) perfusion‐limited model, and permeability‐limited models using (2) ex vivo cotyledon open system apparent clearance, (3) ex vivo cotyledon closed system data fit to a three‐compartment model to estimate clearance, and (4) active transport kinetics and passive clearance. Simulated metformin maternal plasma concentrations (MPCs) and umbilical cord venous plasma concentrations (UCCs) were compared to observed in vivo data from subjects with gestational diabetes mellitus taking metformin 500 mg twice daily. Model selection criteria were determined by the percentage of observed clinical data falling within the 5th to 95th percentiles of the simulated population. Among the approaches, the model that included passive permeability and in vitro intrinsic transporter clearances (Approach 4) best described placental metformin transfer, with 92% of UCCs falling within the 5th to 95th percentiles of the simulated population. Furthermore, maternal uptake transport had the largest influence on predicted UCCs. A two‐fold increase in maternal uptake transport increased the predicted population mean UCC C max by 97%, whereas a 0.5‐fold decrease resulted in a 49% decrease in UCC C max . This refined PBPK model offers a valuable framework for predicting placental transfer and fetal exposure of metformin when placental transporters are altered throughout pregnancy and/or with pathological conditions.

  PublisherOA PDFDOI

• Comparison of Metformin PBPK Models Incorporating Placental Transfer to Predict Fetal and Maternal Exposure

  UNC Libraries · 2025-12-04

  articleOpen access1st authorCorresponding

  Physiologically based pharmacokinetic (PBPK) modeling of placental drug transfer is an evolving tool for predicting fetal drug exposure. In this study, a pregnancy-specific metformin PBPK model was developed,&nbsp;and the following four approaches were evaluated to predict metformin placental transfer: (1) perfusion-limited model, and permeability-limited models using (2) ex&nbsp;vivo cotyledon open system apparent clearance, (3) ex&nbsp;vivo cotyledon closed system data fit to a three-compartment model to estimate clearance, and (4) active transport kinetics and passive clearance. Simulated metformin maternal plasma concentrations (MPCs) and umbilical cord venous plasma concentrations (UCCs) were compared to observed in&nbsp;vivo data from subjects with gestational diabetes mellitus taking metformin 500&thinsp;mg twice daily. Model selection criteria were determined by the percentage of observed clinical data falling within the 5th to 95th percentiles of the simulated population. Among the approaches, the model that included passive permeability and in&nbsp;vitro intrinsic transporter clearances (Approach 4) best described placental metformin transfer, with 92% of UCCs falling within the 5th to 95th percentiles of the simulated population. Furthermore, maternal uptake transport had the largest influence on predicted UCCs. A two-fold increase in maternal uptake transport increased the predicted population mean UCC C_max by 97%, whereas a 0.5-fold decrease resulted in a 49% decrease in UCC C_max. This refined PBPK model offers a valuable framework for predicting placental transfer and fetal exposure of metformin when placental transporters are altered throughout pregnancy and/or with pathological conditions.

  PublisherDOI

• Species-Dependent Metabolism of a Covalent nsP2 Protease Inhibitor with In Vivo Antialphaviral Activity

  Journal of Medicinal Chemistry · 2025-05-12 · 4 citations

  articleOpen access

  RA-0002034 (1) is a potent covalent inhibitor targeting the nsP2 cysteine protease. The species-dependent pharmacokinetics and metabolism of 1 were investigated to evaluate its therapeutic potential. Pharmacokinetic profiling revealed rapid clearance in mice, predominantly mediated by glutathione S-transferase (GST)-catalyzed conjugation. This metabolic liability contrasted with slower clearance observed in human hepatocytes and preclinical species, such as rats, dogs, and monkeys. Cross-species studies confirmed the dominance of GST-driven metabolism in mice, whereas oxidative pathways were more pronounced in dogs. Despite rapid systemic clearance, 1 achieved antiviral efficacy in mice, reducing chikungunya (CHIKV) viral loads in multiple tissues. These cross-species pharmacokinetic and metabolism studies support the continued evaluation of 1 as a potential antialphaviral therapeutic to further define the contribution of hepatic and non-hepatic GST metabolism to its clearance in humans.

  PublisherDOI

• Evaluation of a human 3D multicellular hepatic spheroid model as a platform for studying hepatic transporters

  Cellular and Molecular Life Sciences · 2025-12-30

  articleOpen accessSenior author

  There is growing demand for improved in vitro liver models to better predict in vivo pharmacology, specifically drug disposition mediated by hepatic transporters and assessment of transporter-mediated drug interaction risk. While 2D sandwich-cultured human hepatocytes (SCHH) remain valuable, they are limited to short-term use due to hepatocyte de-differentiation and absence of non-parenchymal cells. Multicellular hepatic spheroids (MHS) offer a promising alternative, but transporter concentrations, functionality, and suitability for hepatobiliary transport studies remain unclear. We evaluated an all-human MHS model, comprised of transporter-certified™ cryopreserved primary human hepatocytes (PHH), Kupffer, stellate, and endothelial cells, for long-term hepatic transporter assessment. Over a 21-day culture period, we monitored transporter concentrations (targeted proteomics), regulation (RNA-seq), localization (immunofluorescence), bile acid profiles (LC–MS/MS), and functional transport (B-CLEAR®). This is the first report of protein concentrations of 13 transporters in MHS over 21 days directly compared to freshly thawed PHH and SCHH from the same donor. Most transporters declined in MHS compared to PHH, while SCHH maintained or increased transporter concentrations by day 5. However, multidrug resistance-associated protein (MRP) 4 and organic solute transporter (OST)-α/β were upregulated in MHS, likely reflecting adaptation to bile acid accumulation. Bile acid profiling confirmed functional synthesis, metabolism and excretion. Functional MRP2 efflux into sealed canalicular compartments was demonstrated with the MRP2 substrate, 5(6)-carboxy-2′,7′-dichlorofluorescein (CDF). Tight junction disruption of canaliculi with Ca2⁺-free buffer resulted in CDF release from canalicular compartments, with partial entrapment within MHS, likely due to the 3D architecture. These findings highlight key strengths and limitations of MHS as a model for assessing hepatobiliary transport.

  PublisherDOI

• Application of a permeability-limited multi-compartment liver (PerMCL) model to predict zonal hepatocellular statin concentrations in metabolic dysfunction-associated steatohepatitis (MASH)

  Drug Metabolism and Pharmacokinetics · 2025-06-01

  article
  PublisherDOI

• Integrated transporter elucidation center: Identifying the SLC and ABC proteome in human placenta

  Drug Metabolism and Pharmacokinetics · 2025-06-01

  article
  PublisherDOI

• Species-Dependent Metabolism of a Covalent nsP2 Protease Inhibitor with In Vivo Antialphaviral Activity

  UNC Libraries · 2025-06-25

  articleOpen accessSenior author

  RA-0002034 (<strong>1</strong>) is a potent covalent inhibitor targeting the nsP2 cysteine protease. The species-dependent pharmacokinetics and metabolism of <strong>1</strong> were investigated to evaluate its therapeutic potential. Pharmacokinetic profiling revealed rapid clearance in mice, predominantly mediated by glutathione <em>S</em>-transferase (GST)-catalyzed conjugation. This metabolic liability contrasted with slower clearance observed in human hepatocytes and preclinical species, such as rats, dogs, and monkeys. Cross-species studies confirmed the dominance of GST-driven metabolism in mice, whereas oxidative pathways were more pronounced in dogs. Despite rapid systemic clearance, <strong>1</strong> achieved antiviral efficacy in mice, reducing chikungunya (CHIKV) viral loads in multiple tissues. These cross-species pharmacokinetic and metabolism studies support the continued evaluation of <strong>1</strong> as a potential antialphaviral therapeutic to further define the contribution of hepatic and non-hepatic GST metabolism to its clearance in humans.

  PublisherDOI

• Visualizing Sodium/Taurocholate Cotransporting Polypeptide (NTCP) Activity and Localization using Optogenetic Tools (Abstract ID: 190717)

  Journal of Pharmacology and Experimental Therapeutics · 2025-03-01

  articleOpen access
  PublisherOA PDFDOI

• Understanding Coproporphyrins and Their Disposition: Coproporphyrinuria is Common, of Diverse Cause, and Rarely Indicates Porphyria

  The American Journal of Medicine · 2025-04-12 · 1 citations

  reviewOpen access
  PublisherOA PDFDOI

• Membrane transporters in drug development and as determinants of precision medicine; an update from the international transporter consortium

  Drug Metabolism and Pharmacokinetics · 2025-06-01

  article1st authorCorresponding
  PublisherDOI

Recent grants

• NIH Grant R21CA106101

  NIH · $263k · 2007

• NIH Grant R56GM041935

  NIH · $365k · 2010

• NIH Grant R29GM041935

  NIH · $499k · 1997

• NIH Grant M01RR000046

  NIH · $3.5M · 2008

• UNC-Duke Collaborative Clinical Pharmacology Postdoctoral Training Program

  NIH · $7.8M · 2011–2026

Frequent coauthors

• Jia Wang

  Harbin Medical University

  90 shared

• Mingming Su

  82 shared

• William J. Brock

  Scientific Consulting Group

  75 shared

• James J. Beaudoin

  University of North Carolina at Chapel Hill

  71 shared

• Ke Lan

  Sichuan University

  70 shared

• Changxiao Liu

  Tianjin Institute of Pharmaceutical Research (China)

  67 shared

• Shanshan Yin

  65 shared

• Pingping Zhu

  Hong Kong Baptist University

  65 shared

Education

• Ph.D., Toxicology

  University of North Carolina at Chapel Hill

  1990

• M.S., Toxicology

  University of North Carolina at Chapel Hill

  1986

• B.S., Toxicology

  University of North Carolina at Chapel Hill

  1984

Awards & honors

• William R. Kenan, Jr. Distinguished Professor