Kenneth E Thummel

University of Washington Seattle, Seattle, Washington, United States

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Publications (204)1009.77 Total impact

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    ABSTRACT: CYP2C19 rs12769205 alters an intron 2 branch point adenine leading to an alternative mRNA in human liver with complete inclusion of intron 2 (exon 2B). rs12769205 changes the mRNA reading frame, introduces 87 amino acids, and leads to a premature stop codon. The 1000 genomes project indicated rs12769205 is in LD with rs4244285 on CYP2C19*2, but found alone on CYP2C19*35 in Blacks. Minigenes containing rs12769205 transfected into HepG2 cells demonstrated this SNP alone leads to exon 2B and decreases CYP2C19 canonical mRNA. A residual amount of CYP2C19 protein was detectable by quantitative proteomics with tandem mass spectrometry in CYP2C19*2/*2 and *1/*35 liver microsomes with an exon 2 probe. However, an exon 4 probe, downstream of rs12769205, but upstream of rs4244285, failed to detect CYP2C19 protein in livers homozygous for rs12769205 demonstrating rs12769205 alone can lead to complete loss of CYP2C19 protein. CYP2C19 genotypes and mephenytoin phenotype were compared in 104 Ethiopians. Poor metabolism of mephenytoin was seen in persons homozygous for both rs12769205 + rs4244285 (CYP2C19*2/*2), but with little effect on mephenytoin disposition of CYP2C19*1/*2, CYP2C19*1/*3 or CYP2C19*1/*35 heterozygous alleles. Extended haplotype homozygosity tests of the Hapmap Yorubans (YRI) showed both haplotypes carrying rs12769205 (CYP2C19*35 and CYP2C19*2) are under significant natural selection, with CYP2C19*35 having a higher REHH score. The phylogenetic tree of the YRI CYP2C19 haplotypes revealed rs12769205 arose first on CYP2C19*35 and that rs4244285 was added later creating CYP2C19*2. In conclusion, rs12769205 is the ancestral polymorphism leading to aberrant splicing of CYP2C19*35 and CYP2C19*2 alleles in liver. The American Society for Pharmacology and Experimental Therapeutics.
    Drug metabolism and disposition: the biological fate of chemicals 05/2015; DOI:10.1124/dmd.115.064428 · 3.33 Impact Factor
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    ABSTRACT: Members of the CYP3A family of drug metabolizing enzymes exhibit developmental changes in expression in human liver characterized by a transition between CYP3A7 and CYP3A4 over the first few years of life. In contrast, the developmental expression of CYP3A5 is less well-understood due to polymorphic expression of the enzyme in human tissues as a result of the prevalence of the CYP3A5*3 allele that leads to alternative splicing. The objective of this paper was to further explore the expression of CYP3A5 and the impact of alternative splicing on the variability of CYP3A5 functional activity in a large bank of human prenatal liver samples (7 to 32 weeks of age post-conception). Expression of normally spliced CYP3A5 mRNA in all human fetal liver samples varied 235-fold, while CYP3A5 SV1 mRNA was only detected in fetal liver samples with at least one CYP3A5*3 allele. Formation of 1'-OH midazolam (MDZ) varied 79-fold, while the ratio of 1'-OH MDZ to 4-OH MDZ varied 8-fold and was dependent on the presence or absence of the CYP3A5*3 allele. Formation of 4-OH MDZ was significantly associated with 1'-OH MDZ (r(2)=0.76, p<0.0001) but varied (36-fold) independently of CYP3A5 genotype or expression. In conclusion, substantial interindividual variability that remains even after stratification for CYP3A5 genotype suggests that factors, such as environmental exposure and epigenetic factors, act in addition to genetic variation to contribute to variability of CYP3A5 expression in human prenatal liver. The American Society for Pharmacology and Experimental Therapeutics.
    Drug metabolism and disposition: the biological fate of chemicals 05/2015; DOI:10.1124/dmd.115.064998 · 3.33 Impact Factor
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    ABSTRACT: Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide interindividual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K-dependent blood clotting factors. We resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation in Anchorage, Alaska and 94 Yup'ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific single nucleotide polymorphisms in larger cohorts of each study population (380 and 350, respectively). We identified high frequencies of the lower-warfarin dose VKORC1 haplotype (-1639G>A and 1173C>T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2, and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity. Overall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the USA, a finding consistent with clinical experience in Alaska.
    Pharmacogenetics and Genomics 05/2015; DOI:10.1097/FPC.0000000000000143 · 3.45 Impact Factor
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    ABSTRACT: Little is known about the impact of alcohol consumption on warfarin safety, or whether demographic, clinical, or genetic factors modify risk of adverse events. We conducted a case-control study to assess the association between screening positive for moderate/severe alcohol misuse and the risk of major bleeding in a community sample of patients using warfarin. The study sample consisted of 570 adult patients continuously enrolled in Group Heath for at least 2 years and receiving warfarin. The main outcome was major bleeding validated through medical record review. Cases experienced major bleeding, and controls did not experience major bleeding. Exposures were Alcohol Use Disorders Identification Test Consumption Questionnaire (AUDIT-C) scores and report of heavy episodic drinking (≥5 drinks on an occasion). The odds of major bleeding were estimated with multivariate logistic regression models. The overall sample was 55% male, 94% Caucasian, and had a mean age of 70 years. Among 265 cases and 305 controls, AUDIT-C scores indicative of moderate/severe alcohol misuse and heavy episodic drinking were associated with increased risk of major bleeding (OR = 2.10, 95% CI = 1.08-4.07; and OR = 2.36, 95% CI = 1.24-4.50, respectively). Stratified analyses demonstrated increased alcohol-related major bleeding risk in patients on warfarin for ≥1 year and in those with a low-dose genotype (CYP2C9*2/*3, VKORC1(1173G>A), CYP4F2*1), but not in other sub-groups evaluated. Alcohol screening questionnaires, potentially coupled with genetic testing, could have clinical utility in selecting patients for warfarin therapy, as well as refining dosing and monitoring practices. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Pharmacoepidemiology and Drug Safety 04/2015; DOI:10.1002/pds.3769 · 3.17 Impact Factor
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    ABSTRACT: Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared to those who are CYP3A5 non-expressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org). This article is protected by copyright. All rights reserved. © 2015 American Society for Clinical Pharmacology and Therapeutics.
    Clinical Pharmacology &#38 Therapeutics 03/2015; DOI:10.1002/cpt.113 · 7.39 Impact Factor
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    ABSTRACT: FFQ data can be used to characterise dietary patterns for diet-disease association studies. In the present study, we evaluated three previously defined dietary patterns - 'subsistence foods', market-based 'processed foods' and 'fruits and vegetables' - among a sample of Yup'ik people from Southwest Alaska. We tested the reproducibility and reliability of the dietary patterns, as well as the associations of these patterns with dietary biomarkers and participant characteristics. We analysed data from adult study participants who completed at least one FFQ with the Center for Alaska Native Health Research 9/2009-5/2013. To test the reproducibility of the dietary patterns, we conducted a confirmatory factor analysis (CFA) of a hypothesised model using eighteen food items to measure the dietary patterns (n 272). To test the reliability of the dietary patterns, we used the CFA to measure composite reliability (n 272) and intra-class correlation coefficients for test-retest reliability (n 113). Finally, to test the associations, we used linear regression (n 637). All factor loadings, except one, in CFA indicated acceptable correlations between foods and dietary patterns (r>0·40), and model-fit criteria were >0·90. Composite and test-retest reliability of the dietary patterns were, respectively, 0·56 and 0·34 for 'subsistence foods', 0·73 and 0·66 for 'processed foods', and 0·72 and 0·54 for 'fruits and vegetables'. In the multi-predictor analysis, the dietary patterns were significantly associated with dietary biomarkers, community location, age, sex and self-reported lifestyle. This analysis confirmed the reproducibility and reliability of the dietary patterns in the present study population. These dietary patterns can be used for future research and development of dietary interventions in this underserved population.
    British Journal Of Nutrition 02/2015; 113(04):1-10. DOI:10.1017/S0007114514003596 · 3.34 Impact Factor
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    ABSTRACT: We sought to discover endogenous urinary biomarkers of human CYP2D6 activity. Healthy pediatric subjects (n = 189) were phenotyped using dextromethorphan and randomized for candidate biomarker selection and validation. Global urinary metabolomics was performed using liquid chromatography quadrupole time-of-flight mass spectrometry. Candidate biomarkers were tested in adults receiving fluoxetine, a CYP2D6 inhibitor. A biomarker, M1 (m/z 444.3102) was correlated with CYP2D6 activity in both the pediatric training and validation sets. Poor metabolizers had undetectable levels of M1, whereas it was present in subjects with other phenotypes. In adult subjects, a 9.56-fold decrease in M1 abundance was observed during CYP2D6 inhibition. Identification and validation of M1 may provide a noninvasive means of CYP2D6 phenotyping.
    Pharmacogenomics 12/2014; 15(16):1947-62. DOI:10.2217/pgs.14.155 · 3.43 Impact Factor
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    ABSTRACT: Glyburide is commonly prescribed for the treatment of gestational diabetes mellitus; however, fetal exposure to glyburide is not well understood and may have short- and long-term consequences for the health of the child. Glyburide can cross the placenta; fetal concentrations at term are nearly comparable to maternal levels. Whether or not glyburide is metabolized in the fetus and by what mechanisms has yet to be determined. In this study, we determined the kinetic parameters for glyburide depletion by CYP3A isoenzymes; characterized glyburide metabolism by human fetal liver tissues collected during the first or early second trimester of pregnancy; and identified the major enzyme responsible for glyburide metabolism in human fetal livers. CYP3A4 had the highest metabolic capacity towards glyburide, followed by CYP3A7 and CYP3A5 (Clint,u = 37.1, 13.0, and 8.7 ml/min/nmol P450, respectively). M5 was the predominant metabolite generated by CYP3A7 and human fetal liver microsomes (HFLMs) with approximately 96% relative abundance. M5 was also the dominant metabolite generated by CYP3A4, CYP3A5, and adult liver microsomes; however, M1-M4 were also present, with up to 15% relative abundance. CYP3A7 protein levels in HFLMs were highly correlated with glyburide Clint, 16α-OH DHEA formation, and 4′-OH midazolam formation. Likewise, glyburide Clint was highly correlated with 16α-OH DHEA formation. Fetal demographics as well as CYP3A5 and CYP3A7 genotype did not alter CYP3A7 protein levels or glyburide Clint. These results indicate that human fetal livers metabolize glyburide predominantly to M5 and that CYP3A7 is the major enzyme responsible for glyburide metabolism in human fetal livers.
    Biochemical Pharmacology 10/2014; DOI:10.1016/j.bcp.2014.09.025 · 4.65 Impact Factor
  • Kenneth Thummel
    2014 Society for Advancement of Hispanics/Chicanos and Native Americans in Science National Conference; 10/2014
  • Wylie Burke, Kenneth Thummel
    JAMA Internal Medicine 10/2014; DOI:10.1001/jamainternmed.2014.3276 · 13.25 Impact Factor
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    ABSTRACT: Gestational diabetes mellitus is a major complication of human pregnancy. The oral clearance (CL) of glyburide, an oral anti-diabetic drug, increases 2-fold in pregnant women during late gestation versus non-pregnant controls. In this study, we examined gestational age-dependent changes in maternal-fetal pharmacokinetics (PK) of glyburide and metabolites in a pregnant mouse model. Non-pregnant and pregnant FVB mice were given glyburide by retro-orbital injection. Maternal plasma was collected over 240 min on gestation days (gd) 0, 7.5, 10, 15 and 19; fetuses were colleceted on gd 15 and 19. Glyburide and metabolites were quantified using HPLC-MS, and PK analyses were performed using a pooled data bootstrap approach. Maternal CL of glyburide increased ≈2-fold on gd 10, 15, and 19 compared to non-pregnant controls. CLint of glyburide in maternal liver microsomes also increased as gestation progressed. Maternal metabolite/glyburide AUC ratios were generally unchanged or slightly decreased throughout gestation. Total fetal exposure to glyburide was < 5% of maternal plasma exposure, and was doubled on gd 19 versus gd 15. Fetal metabolite concentrations were below the limit of assay detection. This is the first evidence of gestational age-dependent changes in glyburide PK. Increased maternal glyburide clearance during gestation is attributable to increased hepatic metabolism. Metabolite elimination may also increase during pregnancy. In the mouse model, fetal exposure to glyburide is gestational age-dependent and low compared to maternal plasma exposure. These results indicate that maternal glyburide therapeutic strategies may require adjustments in a gestational-age dependent manner if these same changes occur in humans.
    Journal of Pharmacology and Experimental Therapeutics 06/2014; 350(2). DOI:10.1124/jpet.114.213470 · 3.86 Impact Factor
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    ABSTRACT: Pharmacogenetics is a subset of personalized medicine that applies knowledge about genetic variation in gene-drug pairs to help guide optimal dosing. There is a lack of data, however, about pharmacogenetic variation in underserved populations. One strategy for increasing participation of underserved populations in pharmacogenetic research is to include communities in the research process. We have established academic-community partnerships with American Indian and Alaska Native people living in Alaska and Montana to study pharmacogenetics. Key features of the partnership include community oversight of the project, research objectives that address community health priorities, and bidirectional learning that builds capacity in both the community and the research team. Engaging the community as coresearchers can help build trust to advance pharmacogenetic research objectives.
    Pharmacogenomics 06/2014; 15(9):1235-41. DOI:10.2217/pgs.14.91 · 3.43 Impact Factor
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    ABSTRACT: Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, have proven efficacy in both lowering low-density-lipoprotein levels and preventing major coronary events, making them one of the most commonly prescribed drugs in the United States. Statins exhibit a class-wide side effect of muscle toxicity and weakness, which has led regulators to impose both dosage limitations and a recall. This review focuses on the best-characterized genetic factors associated with increased statin muscle concentrations, including the genes encoding cytochrome P450 enzymes (CYP2D6, CYP3A4, and CYP3A5), a mitochondrial enzyme (GATM), an influx transporter (SLCO1B1), and efflux transporters (ABCB1 and ABCG2). A systematic literature review was conducted to identify relevant research evaluating the significance of genetic variants predictive of altered statin concentrations and subsequent statin-related myopathy. Studies eligible for inclusion must have incorporated genotype information and must have associated it with some measure of myopathy, either creatine kinase levels or self-reported muscle aches and pains. After an initial review, focus was placed on seven genes that were adequately characterized to provide a substantive review: CYP2D6, CYP3A4, CYP3A5, GATM, SLCO1B1, ABCB1, and ABCG2. All statins were included in this review. Among the genetic factors evaluated, statin-related myopathy appears to be most strongly associated with variants in SLCO1B1.Genet Med advance online publication 8 May 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.41.
    Genetics in medicine: official journal of the American College of Medical Genetics 05/2014; 16(11). DOI:10.1038/gim.2014.41 · 6.44 Impact Factor
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    ABSTRACT: Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25[OH]D3). Effects of low GFR on vitamin D catabolism are less well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25[OH]2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFRs. Cross-sectional study. 9,596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N=1,193), Multi-Ethnic Study of Atherosclerosis (N=6,470), Cardiovascular Health Study (N=932), Seattle Kidney Study (N=289), and Hemodialysis Study (N=712). eGFR. Circulating 24,25(OH)2D3 concentration. GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry. Circulating 24,25(OH)2D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64-0.88). This correlation was weaker with lower eGFRs. Moreover, the increment in 24,25(OH)2D3 concentration associated with higher 25(OH)D3 concentration (slope) was lower with lower eGFRs: 2.06 (95%CI, 2.01-2.10), 1.77 (95%CI, 1.74-1.81), 1.55 (95%CI, 1.48-1.62), 1.17 (95%CI, 1.05-1.29), 0.92 (95%CI, 0.74-1.10), 0.61 (95%CI, 0.22-1.00), and 0.37 (95%CI, 0.35-0.39)ng/mL of 24,25(OH)2D3 per 10ng/mL of 25(OH)D3 for eGFRs≥90, 60-89, 45-59, 30-44, 15-29, and <15mL/min/1.73m(2) and end-stage renal disease treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20ng/mL, mean 24,25(OH)2D3 concentrations were 2.92 (95%CI, 2.87-2.96), 2.68 (95%CI, 2.64-2.72), 2.35 (95%CI, 2.26-2.45), 1.92 (95%CI, 1.74-2.10), 1.69 (95%CI, 1.43-1.95), 1.14 (95%CI, 0.62-1.66), and 1.04 (95%CI,1.02-1.07)ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and circulating parathyroid hormone and fibroblast growth factor 23 concentrations more modestly modified the association of 24,25(OH)2D3 with 25(OH)D3. Lack of direct pharmacokinetic measurements of vitamin D catabolism. Lower eGFR is associated strongly with reduced vitamin D catabolism, as measured by circulating 24,25(OH)2D3 concentration.
    American Journal of Kidney Diseases 04/2014; 64(2). DOI:10.1053/j.ajkd.2014.02.015 · 5.76 Impact Factor
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    ABSTRACT: 25-hydroxyvitamin D3 (25OHD3) is used as a clinical biomarker for assessment of vitamin D status. Blood levels of 25OHD3 represent a balance between its formation rate and clearance by several oxidative and conjugative processes. In the present study, the identity of human UDP-glucuronyltransferases (UGTs) capable of catalyzing the 25OHD3 glucuronidation reaction was investigated. Two isozymes, UGT1A4 and UGT1A3, were identified as the principal catalysts of 25OHD3 glucuronidation in human liver. Three 25OHD3 monoglucuronides (25OHD3-25-glucuronide, 25OHD3-3-glucuronide, and 5,6-trans-25OHD3-25-glucuronide) were generated by recombinant UGT1A4/UGT1A3, human liver microsomes (HLMs), and human hepatocytes. The kinetics of 25OHD3 glucuronide formation in all systems tested conformed to the Michaelis-Menten model. An association between the UGT1A4*3 (Leu48Val) gene polymorphism with the rates of glucuronide formation was also investigated using HLMs isolated from eighty genotyped livers. A variant allele-dose effect was observed; the homozygous UGT1A4*3 livers (GG) had the highest glucuronidation activity, whereas the wild-type (TT) had the lowest activity. Induction of UGT1A4 and UGT1A3 gene expression was also determined in human hepatocytes treated with PXR/CAR agonists such as rifampin, carbamazepine and phenobarbital. While UGT mRNA levels were increased significantly by all of the known PXR/CAR agonists tested, rifampin, the most potent of the inducers, significantly induced total 25OHD3 glucuronide formation activity in human hepatocytes measured after 2 hours, but not 4 and 24 hours of incubation. Finally, the presence of 25OHD3-3-glucuronide in both human plasma and bile was confirmed, suggesting that the glucuronidation pathway might be physiologically relevant and contribute to vitamin D homeostasis in humans.
    Endocrinology 03/2014; 155(6):en20132013. DOI:10.1210/en.2013-2013 · 4.64 Impact Factor
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    ABSTRACT: The influence of warfarin pharmacogenomics on major bleeding risk has been little studied in long-term users and non–specialist care settings. We conducted a case–control study to evaluate associations between CYP2C9*2/*3, VKORC1(1173), and CYP4F2*3 variants and major bleeding among patients treated with warfarin in a community setting. We calculated major bleeding odds ratios, adjusting for race, duration of warfarin use, age, gender, and body mass index. In 265 cases and 305 controls with 3.4 and 3.7 mean years of warfarin use, respectively, CYP4F2*3 was associated with decreased major bleeding risk (odds ratio: 0.62; 95% confidence interval: 0.43–0.91). CYP2C9*2/*3 and VKORC1(1173) had null associations overall, but there was a nonsignificant increase in major bleeding risk in patients with duration <6 months (odds ratio: 1.30; 95% confidence interval: 0.60–2.83; odds ratio: 1.23; 95% confidence interval: 0.57–2.64, respectively). In summary, in the largest study of warfarin pharmacogenomics and major bleeding to date, we found a 38% lower risk in patients with CYP4F2*3, potentially reflecting interaction with warfarin and dietary vitamin K intake and warranting additional evaluation.
    Clinical Pharmacology &#38 Therapeutics 03/2014; 95(6). DOI:10.1038/clpt.2014.26 · 7.39 Impact Factor
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    ABSTRACT: When investigating the potential for xanthine oxidase (XO) mediated metabolism of a new chemical entity in vitro, selective chemical inhibition experiments are typically used. Most commonly, these inhibition experiments are performed using the inhibitor allopurinol (AP) and commercially prepared human liver cytosol (HLC) as the enzyme source. For reasons detailed herein, it is also a common practice to perfuse livers with solutions containing AP prior to liver harvest. The exposure to AP in HLC preparations could obviously pose a problem for measuring in vitro XO activity. To investigate this potential problem, an HPLC-MS/MS assay was developed to determine whether AP and its primary metabolite, oxypurinol, are retained within the cytosol for livers that were treated with AP during liver harvest. Differences in enzymatic activity for XO and aldehyde oxidase (AO) in human cytosol that can be ascribed to AP exposure were also evaluated. The results confirmed the presence of residual AP (some) and oxypurinol (all) human liver cytosol preparations that had been perfused with an AP containing solution. In every case where oxypurinol was detected, XO activity was not observed. In contrast, the presence of AP and oxypurinol did not appear to have an impact on AO activity. Pooled HLC that was purchased from a commercial source also contained residual oxypurinol and did not show any XO activity. In the future, it is recommended that each HLC batch is screened for oxypurinol and/or XO activity prior to testing for XO mediated metabolism of a new chemical entity.
    Drug metabolism and disposition: the biological fate of chemicals 01/2014; 42(4). DOI:10.1124/dmd.113.056374 · 3.33 Impact Factor
  • Kenneth E Thummel, Yvonne S Lin
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    ABSTRACT: The efficacy, safety, and tolerability of drugs are dependent on numerous factors that influence their disposition. A dose that is efficacious and safe for one individual may result in sub-therapeutic or toxic blood concentrations in other individuals. A major source of this variability in drug response is drug metabolism, where differences in pre-systemic and systemic biotransformation efficiency result in variable degrees of systemic exposure (e.g., AUC, C max, and/or C min) following administration of a fixed dose.Interindividual differences in drug biotransformation have been studied extensively. It is well recognized that both intrinsic (such as genetics, age, sex, and disease states) and extrinsic (such as diet, chemical exposures from the environment, and even sunlight) factors play a significant role. For the family of cytochrome P450 enzymes, the most critical of the drug metabolizing enzymes, genetic variation can result in the complete absence or enhanced expression of a functional enzyme. In addition, up- and down-regulation of gene expression, in response to an altered cellular environment, can achieve the same range of metabolic function (phenotype), but often in a less reliably predictable and time-dependent manner. Understanding the mechanistic basis for drug disposition and response variability is essential if we are to move beyond the era of empirical, trial-and-error dose selection and into an age of personalized medicine that brings with it true improvements in health outcomes in the therapeutic treatment of disease.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1113:363-415. DOI:10.1007/978-1-62703-758-7_17 · 1.29 Impact Factor
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    ABSTRACT: Background Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25[OH]D3). Effects of low GFR on vitamin D catabolism are less well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25[OH]2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFRs. Study Design Cross-sectional study. Setting & Participants 9,596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N = 1,193), Multi-Ethnic Study of Atherosclerosis (N = 6,470), Cardiovascular Health Study (N = 932), Seattle Kidney Study (N = 289), and Hemodialysis Study (N = 712). Predictor eGFR. Outcome Circulating 24,25(OH)2D3 concentration. Measurements GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry. Results Circulating 24,25(OH)2D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64-0.88). This correlation was weaker with lower eGFRs. Moreover, the increment in 24,25(OH)2D3 concentration associated with higher 25(OH)D3 concentration (slope) was lower with lower eGFRs: 2.06 (95% CI, 2.01-2.10), 1.77 (95% CI, 1.74-1.81), 1.55 (95% CI, 1.48-1.62), 1.17 (95% CI, 1.05-1.29), 0.92 (95% CI, 0.74-1.10), 0.61 (95% CI, 0.22-1.00), and 0.37 (95% CI, 0.35-0.39) ng/mL of 24,25(OH)2D3 per 10 ng/mL of 25(OH)D3 for eGFRs ≥ 90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2 and end-stage renal disease treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20 ng/mL, mean 24,25(OH)2D3 concentrations were 2.92 (95% CI, 2.87-2.96), 2.68 (95% CI, 2.64-2.72), 2.35 (95% CI, 2.26-2.45), 1.92 (95% CI, 1.74-2.10), 1.69 (95% CI, 1.43-1.95), 1.14 (95% CI, 0.62-1.66), and 1.04 (95% CI,1.02-1.07) ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and circulating parathyroid hormone and fibroblast growth factor 23 concentrations more modestly modified the association of 24,25(OH)2D3 with 25(OH)D3. Limitations Lack of direct pharmacokinetic measurements of vitamin D catabolism. Conclusions Lower eGFR is associated strongly with reduced vitamin D catabolism, as measured by circulating 24,25(OH)2D3 concentration.
    American Journal of Kidney Diseases 01/2014; · 5.76 Impact Factor
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    ABSTRACT: Kidney disease is a public health problem that affects more than 20 million people in the US adult population, yet little is understood about the impact of kidney disease on drug disposition. Consequently there is a critical need to be able to model the human kidney and other organ systems, to improve our understanding of drug efficacy, safety, and toxicity, especially during drug development. The kidneys in general, and the proximal tubule specifically, play a central role in the elimination of xenobiotics. With recent advances in molecular investigation, considerable information has been gathered regarding the substrate profiles of the individual transporters expressed in the proximal tubule. However, we have little knowledge of how these transporters coupled with intracellular enzymes and influenced by metabolic pathways form an efficient secretory and reabsorptive mechanism in the renal tubule. Proximal tubular secretion and reabsorption of xenobiotics is critically dependent on interactions with peritubular capillaries and the interstitium. We plan to robustly model the human kidney tubule interstitium, utilizing an ex vivo three-dimensional modular microphysiological system with human kidney-derived cells. The microphysiological system should accurately reflect human physiology, be usable to predict renal handling of xenobiotics, and should assess mechanisms of kidney injury, and the biological response to injury, from endogenous and exogenous intoxicants.
    Stem Cell Research & Therapy 12/2013; 4 Suppl 1(Suppl 1):S17. DOI:10.1186/scrt378 · 4.63 Impact Factor

Publication Stats

12k Citations
1,009.77 Total Impact Points

Institutions

  • 1986–2015
    • University of Washington Seattle
      • • Department of Pharmaceutics
      • • Department of Pharmacy
      • • Department of Medicinal Chemistry
      Seattle, Washington, United States
  • 2013
    • Trinity Washington University
      Washington, Washington, D.C., United States
  • 2002–2006
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      North Carolina, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2003
    • Duke University
      Durham, North Carolina, United States
  • 2002–2003
    • St. Jude Children's Research Hospital
      • Department of Pharmaceutical Sciences
      Memphis, TN, United States
  • 1995–2001
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2000
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States