K E Thummel

University of Washington Seattle, Seattle, Washington, United States

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Publications (179)942.51 Total impact

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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;
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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; · 3.89 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. · 3.86 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; · 3.92 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; · 5.29 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; · 4.72 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; · 6.85 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; · 3.74 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; · 5.29 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. · 1.29 Impact Factor
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    ABSTRACT: The pharmacokinetics of non-renally cleared drugs in patients with chronic kidney disease is often unpredictable. Some of this variability may be due to alterations in the expression and activity of extra renal drug-metabolizing enzymes and transporters, primarily localized in the liver and intestine. Studies conducted in rodent models of renal failure have shown decreased mRNA and protein expression of many members of the cytochrome P450 enzyme (CYP) gene family and the ATP-binding cassette (ABC) and solute carrier (SLC) gene families of drug transporters. Uremic toxins interfere with transcriptional activation, cause downregulation of gene expression mediated by proinflammatory cytokines, and directly inhibit the activity of the cytochrome P450s and drug transporters. While much has been learned about the effects of kidney disease on non-renal drug disposition, important questions remain regarding the mechanisms of these effects, as well as the interplay between drug-metabolizing enzymes and drug transporters in the uremic milieu. In this review, we have highlighted the existing gaps in our knowledge and understanding of the impact of chronic kidney disease on non-renal drug clearance, and identified areas of opportunity for future research.Kidney International advance online publication, 16 October 2013; doi:10.1038/ki.2013.399.
    Kidney International 10/2013; · 8.52 Impact Factor
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    ABSTRACT: Background/Aims Studies evaluating newly initiated warfarin patients in anticoagulation clinics show that polymorphisms in CYP2C9, VKORC1, and CYP4F2 influence dose requirements, and CYP2C9 variants have increased risk of major bleeding side effects. However, these findings may not be applicable to long-term warfarin users or non-specialist care settings. Within this context, our objective was to evaluate the association between CYP2C9*2 and *3, VKORC1 1173, and CYP4F2*3 variants and major bleeding in long-term warfarin users in a community setting. Methods We used a case-control design and recruited patients from Group Health (GH). Cases experienced a major bleeding event while receiving warfarin. Controls received warfarin on a randomly assigned index date, and had no major bleeding in the prior year. We identified major bleeding with an ICD-9 algorithm, and validated events with chart review. We obtained covariates from GH automated databases and a self-report survey. Our primary analysis used logistic regression to estimate the major bleeding odds ratio (OR) for variants vs. wild type patients. We also conducted an exploratory analysis to estimate the major bleeding OR for patients with variable vs. constant dietary vitamin K intake, stratified by genetic status. Results We enrolled 265 cases and 305 controls with an average of 3.4 and 3.7 years of warfarin use at the index date, respectively. In our primary analysis, the CYP4F2 variant was independently associated with decreased major bleeding risk (OR: 0.62, 0.43-0.91), and CYP2C9 and VKORC1 had null associations. In our exploratory analysis, CYP4F2 wild type patients demonstrated a trend toward increased major bleeding risk with variable vs. constant vitamin K intake (OR = 1.18, 0.64-2.16), while there was a null association in CYP4F2 variants Conclusions In the largest study of warfarin pharmacogenomics and major bleeding to date, we found that a common CYP4F2 variant is associated with a 38% reduction in risk of major bleeding. In contrast, CYP2C9 and VKORC1 variants demonstrated null associations. Our findings may reflect a gene-drug-environment interaction between CYP4F2*3, warfarin, and dietary vitamin K intake. Collectively, our findings expand understanding of genetic risk factors for major bleeding in warfarin therapy, and can potentially inform dosing and monitoring practices pending validation in independent cohorts.
    Clinical Medicine &amp Research 09/2013; 11(3):148.
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    ABSTRACT: OBJECTIVES: Cytochrome P450 enzymes play a dominant role in drug elimination and variation in these genes is a major source of interindividual differences in drug response. Little is known, however, about pharmacogenetic variation in American Indian and Alaska Native (AI/AN) populations. We have developed a partnership with the Confederated Salish and Kootenai Tribes (CSKT) in northwestern Montana to address this knowledge gap. METHODS: We resequenced CYP2D6 in 187 CSKT individuals and CYP3A4, CYP3A5, and CYP2C9 in 94 CSKT individuals. RESULTS: We identified 67 variants in CYP2D6, 15 in CYP3A4, 10 in CYP3A5, and 41 in CYP2C9. The most common CYP2D6 alleles were CYP2D6*4 and *41 (20.86 and 11.23%, respectively). CYP2D6*3, *5, *6, *9, *10, *17, *28, *33, *35, *49, *1xN, *2xN, and *4xN frequencies were less than 2%. CYP3A5*3, CYP3A4*1G, and *1B were detected with frequencies of 92.47, 26.81, and 2.20%, respectively. Allelic variation in CYP2C9 was low: CYP2C9*2 (5.17%) and *3 (2.69%). In general, allele frequencies in CYP2D6, CYP2C9, and CYP3A5 were similar to those observed in European Americans. There was, however, a marked divergence in CYP3A4 for the CYP3A4*1G allele. We also observed low levels of linkage between CYP3A4*1G and CYP3A5*1 in the CSKT. The combination of nonfunctional CYP3A5*3 and putative reduced function CYP3A4*1G alleles may predict diminished clearance of CYP3A substrates. CONCLUSION: These results highlight the importance of carrying out pharmacogenomic research in AI/AN populations and show that extrapolation from other populations is not appropriate. This information could help optimize drug therapy for the CSKT population.
    Pharmacogenetics and Genomics 06/2013; · 3.61 Impact Factor
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    ABSTRACT: The purpose of this study was to determine the impact of CYP3A5 expression on inhibitory potency (Ki or IC50 values) of CYP3A inhibitors, using recombinant CYP3A4 and CYP3A5 (rCYP3A4 and rCYP3A5) and CYP3A5 genotyped human liver microsomes (HLMs). IC50 ratios between rCYP3A4- and rCYP3A5 (rCYP3A5/rCYP3A4) of ketoconazole (KTZ) and itraconazole (ITZ) were 8.5 and 8.8 for midazolam, 4.7 and 9.1 for testosterone, 1.3 and 2.8 for terfenadine, and 0.6 and 1.7 for vincristine, respectively, suggesting substrate and inhibitor-dependent selectivity of the two azoles. Due to the difference in the IC50 values for CYP3A4 and CYP3A5, non-concordant expression of CYP3A4 and CYP3A5 protein can significantly affect the observed magnitude of CYP3A-mediated drug-drug interactions in humans. Indeed, the IC50 values of KTZ and ITZ for CYP3A-catalyzed MDZ and TST metabolism were significantly higher in HLMs with CYP3A5*1/*1 and CYP3A5*1/*3 genotypes than in HLMs with CYP3A5*3/*3 genotype, showing CYP3A5 expression-dependent IC50 values. Moreover, when IC50 values of KTZ and ITZ for different HLMs were kinetically simulated based on CYP3A5 expression level and enzyme-specific IC50 values, a good correlation between the simulated and the experimentally measured IC50 values was observed. Further simulation analysis revealed that both the Ki ratio (for inhibitors) and Vmax/Km ratio (for substrates) between CYP3A4 and CYP3A5 were major factors for CYP3A5 expression-dependent IC50 values. In conclusion, the present study demonstrates that CYP3A5 genotype and expression level have a significant impact on inhibitory potency for CYP3A-catalyzed drug metabolism, but that the magnitude of its effect is inhibitor-substrate pair specific.
    Drug metabolism and disposition: the biological fate of chemicals 05/2013; · 3.74 Impact Factor
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    ABSTRACT: AIM(S): The current investigation aims to provide new insights into fetal exposure to tacrolimus in utero by evaluating maternal and umbilical cord blood (venous and arterial), plasma and unbound concentrations at delivery. This study also presents a case report of tacrolimus excretion via breast milk. METHODS: Maternal and umbilical cord (venous and arterial) samples were obtained at delivery from eight solid organ allograft recipients to measure tacrolimus and metabolite bound and unbound concentrations in blood and plasma. Tacrolimus pharmacokinetics in breast milk were assessed in one subject. RESULTS: Mean (± SD) tacrolimus concentrations at the time of delivery in umbilical cord venous blood (6.6 ± 1.8 ng/mL) were 71 ± 18% (range 45-99%) of maternal concentrations (9.0 ± 3.4 ng/mL). The mean umbilical cord venous plasma (0.09 ± 0.04 ng/mL) and unbound drug concentrations (0.003 ± 0.001 ng/mL) were approximately one fifth of the respective maternal concentrations. Arterial umbilical cord blood concentrations of tacrolimus were 100 ± 12% of umbilical venous concentrations. In addition, infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose. CONCLUSIONS: Differences between maternal and umbilical cord tacrolimus concentrations may be explained in part by placental P-gp function, greater red blood cell partitioning and higher hematocrit levels in venous cord blood. The neonatal drug exposure to tacrolimus via breast milk is very low and likely does not represent a health risk to the breastfeeding infant.
    British Journal of Clinical Pharmacology 03/2013; · 3.69 Impact Factor
  • Nina Isoherranen, Kenneth E Thummel
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    ABSTRACT: There is increasing evidence that pregnancy alters the function of drug-metabolizing enzymes and drug transporters in a gestational-stage and tissue-specific manner. In vivo probe studies have shown that the activity of several hepatic cytochrome P450 enzymes, such as CYP2D6 and CYP3A4, is increased during pregnancy, whereas the activity of others, such as CYP1A2, is decreased. The activity of some renal transporters, including organic cation transporter and P-glycoprotein, also appears to be increased during pregnancy. Although much has been learned, significant gaps still exist in our understanding of the spectrum of drug metabolism and transport genes affected, gestational age-dependent changes in the activity of encoded drug metabolizing and transporting processes, and the mechanisms of pregnancy-induced alterations. In this issue of Drug Metabolism and Disposition, a series of articles is presented that address the predictability, mechanisms, and magnitude of changes in drug metabolism and transport processes during pregnancy. The articles highlight state-of-the-art approaches to studying mechanisms of changes in drug disposition during pregnancy, and illustrate the use and integration of data from in vitro models, animal studies, and human clinical studies. The findings presented show the complex inter-relationships between multiple regulators of drug metabolism and transport genes, such as estrogens, progesterone, and growth hormone, and their effects on enzyme and transporter expression in different tissues. The studies provide the impetus for a mechanism- and evidence-based approach to optimally managing drug therapies during pregnancy and improving treatment outcomes.
    Drug metabolism and disposition: the biological fate of chemicals 02/2013; 41(2):256-262. · 3.74 Impact Factor
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    ABSTRACT: BACKGROUND: Higher concentrations of AM19 and AM1c9, secondary metabolites of cyclosporine A (CsA), have been associated with nephrotoxicity in organ transplant patients. The risk of renal toxicity may depend on the accumulation of CsA and its metabolites in the renal tissue. We evaluated the hypothesis that CYP3A5 genotype, and inferred enzyme expression, affects systemic CsA metabolite exposure and intrarenal CsA accumulation. METHODS: An oral dose of CsA was administered to 24 healthy volunteers who were selected based on their CYP3A5 genotype. CsA and its six main metabolites in whole blood and urine were measured by liquid chromatography-mass spectometry. In vitro incubations of CsA, AM1, AM9, and AM1c with recombinant CYP3A4 and CYP3A5 were performed to evaluate the formation pathways of AM19 and AM1c9. RESULTS: The mean CsA oral clearance was similar between CYP3A5 expressors and nonexpressors. However, compared with CYP3A5 nonexpressors, the average blood area under the concentration-time curve (AUC) for AM19 and AM1c9 was 47.4% and 51.3% higher in CYP3A5 expressors (P=0.040 and 0.011, respectively), corresponding to 30% higher AUCmetabolite/AUCCsA ratios for AM19 and AM1c9 in CYP3A5 expressors. The mean apparent urinary CsA clearance based on a 48-hr collection was 20.4% lower in CYP3A5 expressors compared with CYP3A5 nonexpressors (4.2±1.0 and 5.3±1.3 mL/min, respectively; P=0.037), which is suggestive of CYP3A5-dependent intrarenal CsA metabolism. CONCLUSIONS: At steady state, intrarenal accumulation of CsA and its secondary metabolites should depend on the CYP3A5 genotype of the liver and kidneys. This may contribute to interpatient variability in the risk of CsA-induced nephrotoxicity.
    Transplantation 01/2013; · 3.78 Impact Factor
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    ABSTRACT: OBJECTIVE: An FFQ developed by the Center for Alaska Native Health Research for studies in Yup'ik people includes market foods and subsistence foods such as moose, seal, waterfowl and salmon that may be related to disease risk. Because the FFQ contains >100 food items, we sought to characterize dietary patterns more simply for use in ongoing pharmacogenomics studies. DESIGN: Exploratory factor analysis was used to derive a small number of 'factors' that explain a substantial amount of the variation in the Yup'ik diet. We estimated factor scores and measured associations with demographic characteristics and biomarkers. SETTING: South-west Alaska, USA. SUBJECTS: Yup'ik people (n 358) aged ≥18 years. RESULTS: We identified three factors that each accounted for ≥10 % of the common variance: the first characterized by 'processed foods' (e.g. salty snacks, sweetened cereals); the second by 'fruits and vegetables' (e.g. fresh citrus, potato salad); and the third by 'subsistence foods' (seal or walrus soup, non-oily fish). Participants from coastal communities had higher values for the 'subsistence' factor, whereas participants from inland communities had higher values for the 'fruits and vegetables' factor. A biomarker of marine intake, δ 15N, was correlated with the 'subsistence' factor, whereas a biomarker of corn- and sugarcane-based market food intake, δ 13C, was correlated with 'processed foods'. CONCLUSIONS: The exploratory factor analysis identified three factors that appeared to reflect dietary patterns among Yup'ik based on associations with participant characteristics and biomarkers. These factors will be useful for chronic disease studies in this population.
    Public Health Nutrition 01/2013; · 2.25 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 01/2013; 4 Suppl 1:S17. · 3.65 Impact Factor
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    ABSTRACT: Pregnancy after solid organ transplantation, although considered high risk for maternal, fetal, and neonatal complications, has been quite successful. Tacrolimus pharmacokinetic changes during pregnancy make interpretation of whole blood trough concentrations particularly challenging. There are multiple factors that can increase the fraction of unbound tacrolimus, including but not limited to low albumin concentration and low red blood cell count. The clinical titration of dosage to maintain whole blood tacrolimus trough concentrations in the usual therapeutic range can lead to elevated unbound concentrations and possibly toxicity in pregnant women with anemia and hypoalbuminemia. Measurement of plasma or unbound tacrolimus concentrations for pregnant women might better reflect the active form of the drug, although these are technically challenging and often unavailable in usual clinical practice. Tacrolimus crosses the placenta with in utero exposure being approximately 71% of maternal blood concentrations. The lower fetal blood concentrations are likely due to active efflux transport of tacrolimus from the fetus toward the mother by placental P-glycoprotein. To date, tacrolimus has not been linked to congenital malformations but can cause reversible nephrotoxicity and hyperkalemia in the newborn. In contrast, very small amounts of tacrolimus are excreted in the breast milk and are unlikely to elicit adverse effects in the nursing infant.
    Transplantation 12/2012; · 3.78 Impact Factor

Publication Stats

9k Citations
942.51 Total Impact Points

Institutions

  • 1988–2014
    • University of Washington Seattle
      • • Department of Medicine
      • • Department of Pharmaceutics
      • • Department of Pharmacy
      • • Department of Medicinal Chemistry
      Seattle, Washington, United States
  • 2002–2012
    • St. Jude Children's Research Hospital
      • Department of Pharmaceutical Sciences
      Memphis, TN, United States
  • 2006
    • AstraZeneca
      Tukholma, Stockholm, Sweden
  • 2002–2003
    • University of North Carolina at Chapel Hill
      North Carolina, United States
  • 2001
    • U.S. Food and Drug Administration
      • Center for Drug Evaluation and Research
      Washington, D. C., DC, United States
  • 1995–2001
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2000
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States
  • 1999
    • Vanderbilt University
      • Division of Clinical Pharmacology
      Nashville, MI, United States
    • Indiana University-Purdue University Indianapolis
      • Department of Medicine
      Indianapolis, IN, United States
    • Eli Lilly
      • Department of Drug Disposition
      Indianapolis, IN, United States
    • VA Puget Sound Health Care System
      Washington, Washington, D.C., United States
  • 1997
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States