A5020600016- Drug Transport and Resistance Mechanisms
- Pharmacological Effects and Toxicity Studies
- Pharmacogenetics and Drug Metabolism
- HIV/AIDS drug development and treatment
- Pregnancy and Medication Impact
- Pregnancy and preeclampsia studies
- Adenosine and Purinergic Signaling
- HIV/AIDS Research and Interventions
- HIV Research and Treatment
- Cannabis and Cannabinoid Research
- Organ and Tissue Transplantation Research
- Liver Disease Diagnosis and Treatment
- Pneumocystis jirovecii pneumonia detection and treatment
- Amino Acid Enzymes and Metabolism
- Prenatal Substance Exposure Effects
- Epilepsy research and treatment
- Antibiotics Pharmacokinetics and Efficacy
- Transplantation: Methods and Outcomes
- Drug-Induced Hepatotoxicity and Protection
- Trace Elements in Health
- Renal Transplantation Outcomes and Treatments
- Cystic Fibrosis Research Advances
- Pancreatic function and diabetes
- Gestational Diabetes Research and Management
- Anesthesia and Sedative Agents
University of Washington
2016-2025
University of Chicago
2024
University of Pittsburgh
2009-2023
Washington State University Spokane
2018-2023
Gilead Sciences (United States)
2016-2023
Third Xiangya Hospital
2021-2022
Central South University
2021-2022
City of Hope
2018-2021
Seattle University
1988-2021
Pfizer (United States)
2019-2021
Intestinal transporters are crucial determinants in the oral absorption of many drugs. We therefore studied mRNA expression (N = 33) and absolute protein content 10) clinically relevant healthy epithelium duodenum, proximal distal jejunum ileum, ascending, transversal, descending, sigmoidal colon six organ donors (24–54 years). In small intestine, abundance nearly all proteins ranged between 0.2 1.6 pmol/mg with exception those OCT3 (<0.1 pmol/mg) PEPT1 (2.6–4.9 that accounted for ∼50%...
Importance Controlled clinical laboratory studies have shown that cannabidiol (CBD) can sometimes attenuate or exacerbate the effects of Δ 9-tetrahydrocannabinol ( 9-THC). No evaluated differences in pharmacokinetics (PK) 9-THC and pharmacodynamics (PD) between orally administered cannabis extracts vary with respect to CBD concentrations. Objective To compare PK PD 9-THC-dominant CBD-dominant contained same dose (20 mg). Design, Setting, Participants This randomized trial was a...
Prenatal cannabis use is associated with neurodevelopmental deficits, likely due to exposure the psychoactive cannabinoid, (-)-Δ9-tetrahydrocannabinol, and its active metabolite, (±)-11-OH-Δ9-tetrahydrocannabinol. To determine causality, preclinical studies mimicking human fetal cannabinoid must be conducted. Here we show concentrations across gestation in maternal plasma paired tissues trimester 1 2 umbilical venous 3. The mean ± SD (-)-Δ9-tetrahydrocannabinol brain/maternal 0.50 0.18 (n =...
Numerous knockout mouse studies have revealed that P-glycoprotein (P-gp) significantly limits drug distribution across the blood-brain barrier (BBB). To determine importance of P-gp at human BBB, we developed a state-of-the-art, noninvasive, quantitative imaging technique to measure activity by use carbon 11-labeled verapamil as substrate and cyclosporine (INN, ciclosporin) inhibitor.In brief, 11C-verapamil (approximately 0.2 mCi/kg) was administered healthy volunteers (n = 12 [6 women 6...
The objectives of the study were to evaluate effects pregnancy on CYP3A and P-glycoprotein (P-gp) activities, as measured by disposition midazolam digoxin, respectively. Thirteen women received digoxin (0.25 mg p.o.) (2 in random order, separated 1-2 weeks at 28-32 gestation, same order was repeated 6-10 postpartum. Plasma urine concentrations determined liquid chromatography-mass spectrometry analyzed noncompartmental methods. Midazolam CL/F(unbound) (593 +/- 237 l/min vs. 345 103 l/min; P...
Glyburide's pharmacokinetics (PK) and pharmacodynamics have not been studied in women with gestational diabetes mellitus (GDM). The objective of this study was to assess steady-state PK glyburide, as well insulin sensitivity, β-cell responsivity, overall disposition indices after a mixed-meal tolerance test (MMTT) GDM (n = 40), nonpregnant type 2 (T2DM) 26), healthy pregnant 40, MMTT only). At equivalent doses, glyburide plasma concentrations were ~50% lower than subjects. average umbilical...
Breast cancer resistance protein (BCRP) is a recently discovered ATP-binding cassette drug transporter. Hence, the full spectrum of therapeutic agents that interact with BCRP remains to be elucidated. Because human immunodeficiency virus protease inhibitors (HPIs) are well known P-glycoprotein (P-gp) substrates, and there an overlap in substrate specificity between P-gp BCRP, this study was performed investigate whether HPIs substrates and/or BCRP. First, effect on efflux activity embryonic...
Interindividual variability in protein expression of organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, OATP2B1, and multidrug resistance-linked P-glycoprotein (P-gp) or ABCB1 was quantified frozen human livers (<i>n</i> = 64) cryopreserved hepatocytes 12) by a validated liquid chromatography tandem mass spectroscopy (LC-MS/MS) method. Membrane isolation, sample workup, LC-MS/MS analyses were as described before our laboratory. Briefly, total native membrane proteins, isolated...
Placental efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) protect the developing fetus from exposure to potentially toxic xenobiotics. However, little is known about expression of these in human placentae different gestational ages. Therefore, we quantified P-gp BCRP We also measured various nuclear regulatory factors pregnane xenobiotic factor determine whether their changes with age. Syncitial microvillous plasma membranes were isolated ages...
We quantified, by liquid chromatography tandem mass spectrometry, transporter protein expression of BSEP, MATE1, MRP3, MRP4, NTCP, and OCT1 in our human liver bank (<i>n</i> = 55) determined the relationship between sex, age genotype. These data complement previous work same where we quantified OATPs, BCRP, MDR1, MRP2. In addition, compared interspecies differences hepatobiliary transporters, corresponding to above tissue hepatocytes male beagle dogs, cynomolgus monkeys, Sprague-Dawley rats,...
Studies in animals and postmortem human brain tissue support a role for P-glycoprotein clearance of cerebral β-amyloid across the blood-brain barrier (BBB). We tested hypothesis that BBB activity is diminished Alzheimer disease (AD) by accounting an AD-related reduction regional blood flow (rCBF).We compared mild-AD patients (n = 9) cognitively normal, age-matched controls using PET with labeled substrate, (11)C-verapamil, (15)O-water to measure rCBF. was expressed as (11)C-verapamil...
Human equilibrative nucleoside transporter-3 (hENT3) was recently reported as a pH-dependent, intracellular (lysosomal) transporter capable of transporting anti-human immunodeficiency virus (HIV) dideoxynucleosides (ddNs). Because most anti-HIV ddNs (e.g., zidovudine, AZT) exhibit clinical mitochondrial toxicity, we investigated whether hENT3 facilitates transport into the mitochondria. Cellular fractionation and immunofluorescence microscopy studies in several human cell lines identified...
Protein expression of major hepatic uptake and efflux drug transporters in human pediatric (n = 69) adult 41) livers was quantified by liquid chromatography / tandem mass spectroscopy (LC-MS/MS). Transporter protein OCT1, OATP1B3, P-gp, MRP3 age-dependent. Particularly, significant differences were observed transporter (P < 0.05) between the following age groups: neonates vs. adults (OCT1, P-gp), or infants adolescents and/or children (OATP1B3 (MRP3). OCT1 showed largest increase, almost...
Protein expression of renal uptake and efflux transporters was quantified by quantitative targeted proteomics using the surrogate peptide approach. Renal assessed in this study included organic anion (OAT1–OAT4), cation transporter 2 (OCT2), organic/carnitine (OCTN1 OCTN2), sodium-glucose (SGLT2); P-glycoprotein, breast cancer resistance protein, multidrug proteins (MRP2 MRP4), toxin extrusion (MATE1 MATE2-K). Total membrane isolated from cortex human kidneys (<i>N</i> = 41). The membranes...
Although data are available on the change of expression/activity drug-metabolizing enzymes in liver cirrhosis patients, corresponding transporter protein expression not available. Therefore, using quantitative targeted proteomics, we compared our previous noncirrhotic control livers (n = 36) with major hepatobiliary transporters, breast cancer resistance (BCRP), bile salt export pump (BSEP), multidrug and toxin extrusion 1 (MATE1), resistance-associated (MRP)2, MRP3, MRP4, sodium...
Conducting PK studies in pregnant women is challenging. Therefore, we asked if a physiologically-based pharmacokinetic (PBPK) model could be used to predict the disposition of drugs cleared by multiple CYP enzymes.We expanded and verified our previously published pregnancy PBPK incorporating hepatic CYP2B6 induction (based on vitro data), CYP2C9 phenytoin PK) CYP2C19 suppression proguanil PK), into model. This accounted for gestational age-dependent changes maternal physiology CYP3A, CYP1A2...
This white paper examines recent progress, applications, and challenges in predicting unbound total tissue intra/subcellular drug concentrations using vitro preclinical models, imaging techniques, physiologically based pharmacokinetic (PBPK) modeling. Published examples, regulatory submissions, case studies illustrate the application of different types data development to support modeling decision making for compounds with transporter-mediated disposition, likely disconnects between systemic...