Does in vitro hemolysis affect measurements of plasma apixaban concentration by UPLC-MS and anti-Xa assay?

Introduction: Hemolytic interference may impact various laboratory tests, including coagulation analyses. Apixaban is the most commonly used direct oral anticoagulant in Norway, and there is lacking knowledge on how apixaban concentration measurements might be influenced by hemolysis. Moreover, hemolysis-induced alterations in apixaban levels could potentially impact the risk of bleeding in specific clinical scenarios.

Effect of the NFIB rs28379954 T>C polymorphism on CYP2D6-catalyzed metabolism of solanidine.

Cytochrome P450 2D6 (CYP2D6) is important for metabolism of 20%-25% of all clinically used drugs. Many known genetic variants contribute to the large interindividual variability in CYP2D6 metabolism, but much is still unexplained. We recently described that nuclear factor 1B (NFIB) regulates hepatic CYP2D6 expression with the minor allele of NFIB rs28379954 T>C significantly increasing CYP2D6-mediated risperidone metabolism.

Novel Identification of Cysteinyl Derivatives of Toxic Clozapine Nitrenium Ions and the Effect of Valproic Acid on Metabolite Formation: A Study Using Reprocessed High-Resolution Mass Spectra of Analyzed Therapeutic Drug Monitoring Samples.

Background: Clozapine (CLZ) use is hampered by the risk of granulocyte toxicity, which is associated with the formation of nitrenium ions and the concurrent use of valproic acid (VPA). These highly reactive nitrenium ions cannot be measured in vivo. Instead, deactivated cysteinyl conjugates may potentially be detected.

Evidence for solanidine as a dietary CYP2D6 biomarker: Significant correlation with risperidone metabolism.

Aims: The extensive variability in cytochrome P450 2D6 (CYP2D6) metabolism is mainly caused by genetic polymorphisms. However, there is large, unexplained variability in CYP2D6 metabolism within CYP2D6 genotype subgroups. Solanidine, a dietary compound found in potatoes, is a promising phenotype biomarker predicting individual CYP2D6 metabolism.

Prediction of CYP2D6 poor metabolizers by measurements of solanidine and metabolites-a study in 839 patients with known CYP2D6 genotype.

Purpose: Poor metabolizers (PMs) of the highly polymorphic enzyme CYP2D6 are usually at high risk of adverse effects during standard recommended dosing of CYP2D6-metabolized drugs. We studied if the metabolism of solanidine, a dietary compound found in potatoes, could serve as a biomarker predicting the CYP2D6 PM phenotype for precision dosing.

Methods: The study included 839 CYP2D6-genotyped patients who were randomized by a 4:1 ratio into test or validation cohorts.

Metabolite Profiling of Clozapine in Patients Switching Versus Maintaining Treatment: A Retrospective Pilot Study.

Purpose/background: Pharmacokinetics may be of relevance for the risk of clozapine discontinuation. We compared metabolite profiles, accounting for smoking habits, in patients switching versus maintaining clozapine treatment at therapeutic concentrations.

Methods/procedures: Adult patients with clozapine serum levels above 1070 nmol/L (350 ng/mL) were retrospectively included from a Norwegian therapeutic drug monitoring service during 2018-2020.

Correlations between 4β-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range.

Purpose: Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4β-hydroxycholesterol (4βOHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4βOHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range.

In Vitro Apixaban Removal By CytoSorb Whole Blood Adsorber: An Experimental Study.

Objectives: The use of unopposed oral anticoagulants while undergoing cardiothoracic surgery is associated with severe bleeding and increased morbidity. The aim of this experimental study was to examine if the apixaban concentration in reconstituted blood could be reduced in an in vitro setup by the use of CytoSorb whole blood adsorber, and to study how this affected global coagulation assays.

Design And Setting: An experimental study performed in a laboratory.

Effects of a Novel UGT2B Haplotype and UGT1A4*3 Allele Variants on Glucuronidation of Clozapine In vivo.

Background: Glucuronidation is an important metabolic pathway of clozapine (CLZ), but the impact of various uridine 5'diphospho-glucuronosyltransferases (UGT) polymorphisms on the exposure and metabolism of CLZ in vivo is unclear.

Objective: The objective of this study was to investigate the impact of UGT2B haplotype and UGT1A4*3 allele variants on the formation of CLZ glucuronide metabolites (5N- and N+-glucuronide) and CLZ exposure in patients' serum after adjusting for sex, age, and smoking habits.

Methods: The study was based on serum samples from CLZ-treated patients (n=79) subjected to routine therapeutic drug monitoring (TDM) at Diakonhjemmet Hospital, Oslo, Norway.

Effect of Valproic Acid on the Metabolic Spectrum of Clozapine in Patients With Schizophrenia.

Background: Valproic acid (VPA) is frequently used with clozapine (CLZ) as mood stabilizer and/or seizure prophylaxis. Valproic acid is known to reduce N-desmethylclozapine (N-DMC) but not CLZ levels. This leads to the hypothesis that VPA induces the CLZ metabolism via non-N-desmethylation pathways.

Short- and long-term effects of body weight loss following calorie restriction and gastric bypass on CYP3A-activity - a non-randomized three-armed controlled trial.

It remains uncertain whether pharmacokinetic changes following Roux-en-Y gastric bypass (RYGB) can be attributed to surgery-induced gastrointestinal alterations per se and/or the subsequent weight loss. The aim was to compare short- and long-term effects of RYGB and calorie restriction on CYP3A-activity, and cross-sectionally compare CYP3A-activity with normal weight to overweight controls using midazolam as probe drug. This three-armed controlled trial included patients with severe obesity preparing for RYGB (n = 41) or diet-induced (n = 41) weight-loss, and controls (n = 18).

Validation of a Population Pharmacokinetic Model of Vortioxetine Using Therapeutic Drug Monitoring Data.

Introduction: Vortioxetine is an antidepressant primarily metabolized by the polymorphic enzyme cytochrome P450 (CYP) 2D6. A population pharmacokinetic (popPK) model of vortioxetine and its CYP2D6-dependent metabolite was recently published.

Objective: The aim of the current study was to assess the predictive performance of the popPK model using vortioxetine concentration measurements from a clinical setting.

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Characterizing the pharmacokinetic properties of drug candidates represents an essential task during drug development. In the past, liver microsomes and primary suspended hepatocytes have been extensively used for this purpose, but their relatively short stability limits the applicability of such systems for drug compounds with low metabolic turnover. In the present study, we used 3D primary human hepatocyte spheroids to predict the hepatic clearance of seven drugs with low to intermediate clearance in humans.

Substantial Differences in Serum Concentrations of Psychoactive Drugs Measured in Samples Stored for 2 Days or More on Standard Serum Tubes Versus Serum Tubes Containing Gel Separators.

Background: Drugs may potentially adsorb to blood collection tubes containing gel separators in the preanalytical phase of therapeutic drug monitoring. The aim of this study was to compare measured concentrations of 28 psychoactive drugs and 13 metabolites in spiked serum samples stored on standard (plain) tubes versus barrier gel tubes during a 2-6-day period at room temperature.

Methods: Drug-free ("blank") serum samples spiked with mixes of antidepressants, antipsychotics, or mood stabilizers (valproic acid and lamotrigine), including relevant metabolites, were transferred to tubes with and without gel, that is, BD Vacutainer SST II Advance gel tubes and BD Vacutainer Glass Serum Tubes (Becton-Dickinson Company, Plymouth, United Kingdom).

Associations between Cytokine Levels and CYP3A4 Phenotype in Patients with Rheumatoid Arthritis.

Systemic inflammation has been linked to suppressed CYP3A4 activity. The aim of this study was to examine associations between levels of a broad selection of cytokines and CYP3A4 phenotype in patients with rheumatoid arthritis (RA). The study included 31 RA patients treated with tumor necrosis factor (TNF)- inhibitors.

Comparison of CYP3A4-Inducing Capacity of Enzyme-Inducing Antiepileptic Drugs Using 4β-Hydroxycholesterol as Biomarker.

Background: Enzyme-inducing antiepileptic drugs (EIAEDs) are among the clinically most important inducers of cytochrome P450 (CYP) 3A4, but there is limited evidence regarding the comparative potency of each EIAED in raising CYP3A4 activity. The aim of this study was to estimate CYP3A4-inductive potency of EIAEDs by comparing CYP3A4 activity in patients treated with carbamazepine, phenobarbital, or phenytoin.

Methods: Residual serum samples from patients treated with EIAEDs or levetiracetam were collected from a therapeutic drug monitoring service for analysis of 4β-hydroxycholesterol (4βOHC), which is an indicator of CYP3A4 activity.