Lower CYP2C9 activity in Turkish patients with Behçet’s disease compared to healthy subjects: a down-regulation due to inflammation?

Göktaş, Mustafa Tuğrul; Hatta, Fazleen Haslinda Mohd; Karaca, Ozgur; Kalkisim, Said; Kılıç, Levent; Akdoğan, Ali; Babaoğlu, Melih O.; Bozkurt, Atilla; Helldén, Anders; Yaşar, Ümit

doi:10.1007/s00228-015-1899-7

Cited by 14 publications

(22 citation statements)

References 86 publications

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“…Phenoconversion is also observed during inflammatory comorbidities . For example, patients with Behçet's disease have been shown to have lower CYP2C9 activity …”

Section: Discussionmentioning

confidence: 99%

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

Shah

2020

J Clin Pharm Ther

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What is known and objective: Despite an apparently sound pharmacological basis, clinical studies of genotype-guided warfarin dosing have yielded mixed and conflicting results, leading to reluctance in its clinical implementation. The objective of this critique is to re-evaluate key warfarin pharmacogenetic studies with a view to explaining why this may be so. Methods:Major widely-cited warfarin pharmacogenetic studies as well as recent meta-analyses were identified and a critical analysis of these was undertaken to identify factors that may account for poor clinical implementation of pre-treatment genotyping. Results and discussion: Critical examination of major warfarin pharmacogenetic studies identified a number of methodological concerns such as marked variations in study designs with different variously-defined measures of outcome. Genotype testing involved only a limited number of CYP2C9/VKORC1 alleles. Claims of benefits of genotyping are based almost exclusively on INR-related parameters which are known to be highly time-labile and of limited value in predicting clinical risk orbenefit. This is evidenced by lack of any significant effect of genotyping on rates of bleeding or thromboembolic events. Neither have the effects of potential phenoconversion or medication non-adherence in study populations been adequately investigated. Although the effect of ethnicity/race is now better characterised, studies lack the power to determine whether any benefits claimed are indication-sensitive. What is new and conclusion:Since 60% of inter-individual variability in warfarin dose/ response is due to other factors (many of which are non-genetic), expectations of eliminating this variability simply by CYP2C9/VKORC1 genotyping are over-optimistic and efforts cost-ineffective. Real-world studies have not always corroborated trialsbased claims of clinical benefit. It is time to consider redirecting scarce resources away from the study of warfarin pharmacogenetics to pharmacogenetic research of potentially greater clinical relevance.

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“…Phenoconversion is also observed during inflammatory comorbidities . For example, patients with Behçet's disease have been shown to have lower CYP2C9 activity …”

Section: Discussionmentioning

confidence: 99%

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

Shah

2020

J Clin Pharm Ther

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“…In this study, patients with BD had about 2.5‐fold increased lansoprazole metabolic ratio compared to the controls suggesting that CYP2C19 activity is markedly reduced in these patients. Consistent with this finding, in our previous study , we reported a significantly decreased CYP2C9 activity in the same patients with BD. Immune cytokine reactions in BD might have caused the down‐regulation of CYP2C9 as well as of the CYP2C19 activity.…”

Section: Discussionmentioning

confidence: 99%

“…In another in vivo study, colchicine did not significantly change CYP2C19 activity in rat . We also recently showed that colchicine does not have any significant effect on losartan metabolism, which is a probe reaction for phenotyping of the CYP2C9 in vivo in human beings . In this study, we demonstrated that colchicine did not exert any change in the CYP2C19 activity of six patients who used the drug for 2 weeks.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we reported the relation between CYP2C9 polymorphisms and BD . In that study, the patients with BD and healthy controls received a 50‐mg single oral dose of losartan before going to bed, and urine was collected for 8 hr after administration of the drug . In the morning, the subjects brought the urine samples and additionally received 30 mg lansoprazole after an overnight fasting.…”

Section: Methodsmentioning

confidence: 99%

“…TNF‐α and IL‐6) have been linked to a significant decrease up to 50% in mRNA levels of CYP2C9 and CYP2C19 in human hepatocytes . We have in a previous study in BD patients and healthy controls shown that the rate of metabolism of losartan by CYP2C9 in patients with BD presumably by down‐regulation due to inflammation . In that study, the same subjects also received lansoprazole to evaluate the activity of CYP2C19.…”

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confidence: 99%

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Decreased Activity and Genetic Polymorphisms ofCYP2C19 in Behçet's Disease

Göktaş

Karaca

Kalkisim

et al. 2017

Basic Clin Pharma Tox

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Behçet's disease (BD) is a systemic autoimmune disorder. Cytochrome P450 enzymes (CYPs) are responsible for various drug metabolism reactions as well as those of endogenous substances which may be associated with autoimmune disease susceptibility. Recently, we reported that in patients with BD, CYP2C9 seems to be down-regulated due to inflammation. In the same Turkish patients with BD, we investigated whether also CYP2C19 activity is decreased. Lansoprazole (30 mg) was given as a probe drug to evaluate CYP2C19 activity in 59 patients with BD and 27 healthy control volunteers. An HPLC method was used to determine plasma lansoprazole and its metabolite, 5-hydroxy lansoprazole, concentrations. The genotyping for CYP2C19 *2, *3 and *17 polymorphisms was made using PCR-RFLP. The median lansoprazole/5-hydroxy lansoprazole metabolic ratio (MR) in patients with BD was 2.6-fold higher as compared to the healthy control group (p = 0.001, 22.6 (1.3-26) and 8.8 (0.5-140) as median and range, respectively). The CYP2C19*17*17 genotype frequency was found to be significantly less in the BD group as compared to the healthy controls (1.7% versus 14.8% in controls, p = 0.01). Additionally, colchicine treatment did not affect the CYP2C19 enzyme activity in six patients (p = 0.43). In conclusion, the patients with BD had lower CYP2C19 enzyme activity and lower frequency of the CYP2C19*17 allele as compared to those of the healthy controls. Further studies are warranted on the mechanisms underlying this relation. This study should also be applied to other autoimmune diseases similarly characterized by local or systemic inflammation.

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Impact of Acute Inflammation on Cytochromes P450 Activity Assessed by the Geneva Cocktail

Lenoir

Daali

Rollason

et al. 2021

Clin Pharma and Therapeutics

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Cytochromes P450 (CYP) are subject to important interindividual variability in their activity due to genetic and environmental factors and some diseases. Limited human data support the idea that inflammation downregulates CYP activities. Our study aimed to evaluate the impact of orthopedic surgery (acute inflammation model) on the activity of six human CYP. This prospective observational study was conducted in 30 patients who underwent elective hip surgery at the Geneva University Hospitals in Switzerland. The Geneva phenotyping cocktail containing caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, and midazolam as probe drugs respectively assessing CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A activities was administered orally before surgery, day 1 (D1) and 3 (D3) postsurgery and at discharge. Capillary blood samples were collected 2 hours after cocktail intake to assess metabolic ratios (MRs). Serum inflammatory markers (CRP, IL-6, IL-1β, TNF-α, and IFN-γ) were also measured in blood. CYP1A2 MRs decreased by 53% (P < 0.0001) between baseline and the nadir at D1. CYP2C19 and CYP3A activities (MRs) decreased by 57% (P = 0.0002) and 61% (P < 0.0001), respectively, with the nadir at D3. CYP2B6 and CYP2C9 MRs increased by 120% (P < 0.0001) and 79% (P = 0.018), respectively, and peaked at D1. Surgery did not have a significant impact on CYP2D6 MR. Hip surgery was a good acute inflammation model as CRP, IL-6, and TNF-α peak levels were reached between D1 and day 2 (D2). Acute inflammation modulated CYP activity in an isoform-specific manner, with different magnitudes and kinetics. Acute inflammation may thus have a clinically relevant impact on the pharmacokinetics of these CYP substrates.

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Lower CYP2C9 activity in Turkish patients with Behçet’s disease compared to healthy subjects: a down-regulation due to inflammation?

Cited by 14 publications

References 86 publications

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

Decreased Activity and Genetic Polymorphisms ofCYP2C19 in Behçet's Disease

Impact of Acute Inflammation on Cytochromes P450 Activity Assessed by the Geneva Cocktail

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