Introduction: Intestinal permeability is characterized by a loss of the gut epithelial wall integrity allowing different sizes of compounds (food antigens, commensal or pathogenic bacteria, and their metabolites) to enter the systemic circulation. In addition, we observed decreased KDR methylation (by 0.71%, p=0.003) in cases compared to non-bleeding patients at 7 days of therapy. No differences were found for NOS3 PRDI/II and KDR methylation. When patients were categorized into experiencing bleeding events (cases) or not (controls), in cases NOS3 CRE was demethylated from t0 to t2 (-16.36% in cases vs. In patient cohort, DOAC therapy did not alter NOS3 or KDR methylation at different timepoints. Percentage of DNA methylation of NOS3 and KDR at baseline did not differ between AF patients and non-AF controls. In both patients and controls, NOS3 CRE and PRDI/II elements were heavily methylated, while KDR promoter was lightly methylated. In regression analysis adjusted for DOAC dose, gender, age, co-morbidities and bleeding-inducing drug interactions, hypertension increased risk for bleeding (OR 28.587, 95% C.I. A total of 15 minor bleeding events occurred. Results: In our study, no major bleeding or thrombotic events were recorded. CYP3A phenotype and SNPs tested had no significant impact on the pharmacokinetics of both molecules of both molecules. AUCfexofenadine per log10 (232.51 (105.69 to 359.33) p=0.0004) also had a significant impact on rivaroxaban AUC. The covariables were the weight, age, gender, GFR (Cockcroft), ALAT level, dose, log10(MRmidazolam) and log10(AUCfexofenadine). A linear mixed model for apixaban and rivaroxaban AUC predicted 40% and 18% of the variability, respectively. Results: Substantial interindividual variability was observed in dose-normalized blood concentrations and AUC of apixaban (117.4±55.9 ng/mL) and rivaroxaban (once a day: 21.3☑2.4 ng/mL and twice a day: 28.3☘.9 ng/mL), as well as CYP3A (0.45☐.42 for apixaban cohort and 0.44☐.44 for rivaroxaban cohort) and P-gp (222.8☒19.4 for apixaban cohort and 200.1☑50 for rivaroxaban cohort) phenotypic activities.
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