Browsing by Author "Kreutz, Yvonne"

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    CYP2B6 Genotype‐Dependent Inhibition of CYP1A2 and Induction of CYP2A6 by the Antiretroviral Drug Efavirenz in Healthy Volunteers
    (ASCPT, 2019) Metzger, Ingrid F.; Dave, Nimita; Kreutz, Yvonne; Lu, Jessica B. L.; Galinsky, Raymond E.; Desta, Zeruesenay; Pharmacology and Toxicology, School of Medicine
    We investigated the effect of efavirenz on the activities of cytochrome P450 (CYP)1A2, CYP2A6, xanthine oxidase (XO), and N‐acetyltransferase 2 (NAT2), using caffeine as a probe. A single 150 mg oral dose of caffeine was administered to healthy volunteers (n = 58) on two separate occasions; with a single 600 mg oral dose of efavirenz and after treatment with 600 mg/day efavirenz for 17 days. Caffeine and its metabolites in plasma and urine were quantified using liquid chromatography/tandem‐mass spectrometry. DNA was genotyped for CYP2B6*4 (785A>G), CYP2B6*9 (516G>T), and CYP2B6*18 (983T>C) alleles using TaqMan assays. Relative to single‐dose efavirenz treatment, multiple doses of efavirenz decreased CYP1A2 (by 38%) and increased CYP2A6 (by 85%) activities (P < 0.05); XO and NAT2 activities were unaffected. CYP2B6*6*6 genotype was associated with lower CYP1A2 activity following both single and multiple doses of efavirenz. No similar association was noted for CYP2A6 activity. This is the first report showing that efavirenz reduces hepatic CYP1A2 and suggesting chronic efavirenz exposure likely enhances the elimination of CYP2A6 substrates. This is also the first to report the extent of efavirenz–CYP1A2 interaction may be efavirenz exposure‐dependent and CYP2B6 genotype‐dependent.
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    Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response
    (Dove Press, 2013-12-09) Kreutz, Rolf P.; Owens, Janelle; Jin, Yan; Nystrom, Perry; Desta, Zeruesenay; Kreutz, Yvonne; Breall, Jeffrey A.; Li, Lang; Chiang, ChienWei; Kovacs, Richard J.; Flockhart, David A.; Medicine, School of Medicine
    Recent candidate gene studies using a human liver bank and in vivo validation in healthy volunteers identified polymorphisms in cytochrome P450 (CYP) 3A4 gene (CYP3A4*22), Ah-receptor nuclear translocator (ARNT), and peroxisome proliferator-activated receptor-α (PPAR-α) genes that are associated with the CYP3A4 phenotype. We hypothesized that the variants identified in these genes may be associated with altered clopidogrel response, since generation of clopidogrel active metabolite is, partially mediated by CYP3A activity. Blood samples from 211 subjects, of mixed racial background, with established coronary artery disease, who had received clopidogrel, were analyzed. Platelet aggregation was determined using light transmittance aggregometry (LTA). Genotyping for CYP2C19*2, CYP3A4*22, PPAR-α (rs4253728, rs4823613), and ARNT (rs2134688) variant alleles was performed using Taqman® assays. CYP2C19*2 genotype was associated with increased on-treatment platelet aggregation (adenosine diphosphate 20 μM; P=0.025). No significant difference in on-treatment platelet aggregation, as measured by LTA during therapy with clopidogrel, was demonstrated among the different genotypes of CYP3A4*22, PPAR-α, and ARNT. These findings suggest that clopidogrel platelet inhibition is not influenced by the genetic variants that have previously been associated with reduced CYP3A4 activity.
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    Efavirenz inhibits the human ether-a-go-go related current (hERG) and induces QT interval prolongation in CYP2B6*6*6 allele carriers
    (Wiley, 2016-10) Abdelhady, Ahmed M.; Shugg, Tyler; Thong, Nancy; Li Lu, Jessica Bo; Kreutz, Yvonne; Jaynes, Heather A.; Robarge, Jason D.; Tisdale, James E.; Desta, Zeruesenay; Overholser, Brian R.; Pharmacology and Toxicology, School of Medicine
    Background Efavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele. Objective The primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening. Methods EFV was administered to healthy volunteers (n=57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression. Results EFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences ΔΔQTcF were observed at 6 hrs (14 ms; 95% CI [1; 27]), 12 hrs (18 ms; 95% CI [−4; 40] and 18 hrs (6 ms; 95% CI [−1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 µg/mL significantly inhibited outward hERG tail currents (P<0.05). Conclusions This study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG.
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    Efavirenz-mediated induction of omeprazole metabolism is CYP2C19 genotype-dependent
    (Springer Nature, 2014) Michaud, Veronique; Kreutz, Yvonne; Skaar, Todd; Ogburn, Evan; Thong, Nancy; Flockhart, David A.; Desta, Zeruesenay; Medicine, School of Medicine
    Efavirenz increases CYP2C19- and CYP3A-mediated omeprazole metabolism. We hypothesized that CYP2C19 and CYP2B6 genetic polymorphisms influence the extent of induction of omeprazole metabolism by efavirenz. Healthy subjects (n=57) were administered a single 20mg oral dose of omeprazole with a single dose (600mg) or after multiple doses (600mg/day for 17 days) of efavirenz. DNA was genotyped for CYP2C19*2, *3 and *17 alleles and CYP2B6*6, *4 and *9 alleles using Taqman assays. Omeprazole, its enantiomers and metabolites were measured by LC/MS/MS. Our results showed that efavirenz increased omeprazole clearances in all CYP2C19 genotypes in non-stereoselective manner, but the magnitude of induction was genotype-dependent. Metabolic ratios of 5-hydroxylation of omeprazole were reduced in extensive and intermediate metabolizers of CYP2C19 (p<0.05). No significant associations were observed between CYP2B6 genotypes and induction by efavirenz on omeprazole metabolism. Our data indicate how interplays between drug interactions and CYP2C19 genetic variations may influence systemic exposure of CYP2C19 substrates.
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    Platelet Factor XIIIa Release During Platelet Aggregation and Plasma Clot Strength Measured by Thrombelastography in Patients with Coronary Artery Disease Treated with Clopidogrel.
    (Taylor & Francis, 2015) Kreutz, Rolf P.; Owens, Janelle; Lu, Deshun; Nystrom, Perry; Jin, Yan; Kreutz, Yvonne; Desta, Zeruesenay; Flockhart, David A.; Department of Medicine, IU School of Medicine
    It has been estimated that up to half of circulating Factor XIIIa (FXIIIa) is stored in platelets. The release of FXIIIa from platelets upon stimulation with ADP in patients with coronary artery disease treated with dual antiplatelet therapy has not been previously examined. Samples from 96 patients with established coronary artery disease treated with aspirin and clopidogrel were examined. Platelet aggregation was performed by light transmittance aggregometry (LTA) in platelet rich plasma (PRP) with platelet poor plasma (PPP) as reference and ADP 5μM as agonist. Kaolin activated TEG was performed in citrate PPP. PRP after aggregation was centrifuged and plasma supernatant (PSN) collected. FXIIIa was measured in PPP and PSN.Platelet aggregation after stimulation with ADP 5μM resulted in 24% additional FXIIIa release in PSN as compared to PPP (99.3 ± 27 vs. 80.3 ± 24 %, p<0.0001). FXIIIa concentration in PSN correlated with maximal plasma clot strength (TEG-G) (r=0.48, p<0.0001), but not in PPP (r=0.15, p=0.14). Increasing quartiles of platelet derived FXIIIa were associated with incrementally higher TEG-G (p=0.012). FXIIIa release was similar between clopidogrel responders and non-responders (p=0.18). In summary, platelets treated with aspirin and clopidogrel release a significant amount of FXIIIa upon aggregation by ADP. Platelet derived FXIIIa may contribute to differences in plasma TEG-G, and thus in part provide a mechanistic explanation for high clot strength observed as a consequence of platelet activation. Variability in clopidogrel response does not significantly influence FXIIIa release from platelets.