Search

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity; however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentration ratios were perfectly explained (r2 > 0.99) in a multilinear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this study, the liver:plasma concentration ratio of perfluoroheptanoic acid (PFHpA) was considerably higher than the liver:plasma concentration ratio of other PFAS congeners. Comparing the MLR model with an equilibrium mass balance model (MBM) suggested that complex kinetic transport processes are driving the unexpectedly high liver:plasma concentration ratio of PFHpA. Intratissue MBM modeling pointed to membrane lipids as the tissue constituents that drive the liver accumulation of long-chain, hydrophobic PFAS, whereas albumin binding of hydrophobic PFAS dominated PFAS distribution in plasma. The liver:plasma concentration data set, empirical MLR model, and mechanistic MBM modeling allow the prediction of liver from plasma concentrations measured in human cohort studies. Our study demonstrates that combining biomonitoring data with mechanistic modeling can identify underlying mechanisms of internal distribution and specific target organ toxicity of PFAS in humans.

Paclitaxel-induced peripheral neuropathy (PIPN) is a common and dose-limiting adverse event. The role of P-glycoprotein (P-gp) in the neuronal efflux of paclitaxel was assessed using a translational approach. SH-SY5Y cells were differentiated to neurons and paclitaxel toxicity in the absence and presence of a P-gp inhibitor was determined. Paclitaxel caused marked dose-dependent toxicity in SH-SY5Y-derived neurons. Paclitaxel neurotoxicity was exacerbated with concomitant P-gp inhibition by valspodar and verapamil, consistent with increased intracellular accumulation of paclitaxel. Patients with cancer treated with paclitaxel and P-gp inhibitors had a 2.4-fold (95% confidence interval (CI) 1.3-4.3) increased risk of peripheral neuropathy-induced dose modification while a 4.7-fold (95% CI 1.9-11.9) increased risk for patients treated with strong P-gp inhibitors was observed, and a 7.0-fold (95% CI 2.3-21.5) increased risk in patients treated with atorvastatin. Atorvastatin also increased neurotoxicity by paclitaxel in SH-SY5Y-derived neurons. Clinicians should be aware that comedication with P-gp inhibitors may lead to increased risk of PIPN.

Aim: We aimed to assess if dicloxacillin/flucloxacillin reduces the therapeutic efficacy of direct oral anticoagulants (DOACs) and the underlying molecular mechanism. Methods: In a randomized, crossover study, we assessed whether dicloxacillin reduces oral absorption of drugs through P‐glycoprotein (P‐gp) during 10 and 28 days of treatment. To study the impact of dicloxacillin/flucloxacillin on intestinal and hepatic expression of P‐gp in vitro, we usd LS174T cells and 3D spheroids of primary human hepatocytes. Finally, we used nationwide Danish health registries and the UK's Clinical Practice Research Datalink to estimate hazard ratios (HRs) for the risk of stroke and systemic embolism following dicloxacillin/flucloxacillin exposure among DOAC users, using phenoxymethylpenicillin and amoxicillin as active comparators. Results: Dicloxacillin reduced the area under the curve of dabigatran to a geometric mean ratio 10 days of 0.67 (95% confidence interval [CI]: 0.42–1.1) and geometric mean ratio 28 days of 0.72 (95% CI: 0.39–1.4), suggesting reduced oral absorption via increased P‐gp expression. In vitro, dicloxacillin raised P‐gp expression in both intestinal and liver cells, while flucloxacillin only affected liver cells. In the pharmacoepidemiologic study, dicloxacillin and flucloxacillin were not associated with increased risk of stroke/systemic embolism (dicloxacillin vs. phenoxymethylpenicillin HR: 0.93, 95% CI: 0.72–1.2; flucloxacillin vs. amoxicillin HR: 0.89, 95% CI: 0.51–1.5). Conclusions: Dicloxacillin increases expression of intestinal P‐gp, leading to reduced oral absorption of dabigatran. However, concomitant use of dicloxacillin/flucloxacillin was not associated with stroke and systemic embolism among DOAC users, suggesting no clinical impact from the drug–drug interaction between dicloxacillin/flucloxacillin and DOACs. [ABSTRACT FROM AUTHOR]

Long‐term sample stability of five atypical antipsychoticdrugs risperidone, paliperidone, clozapine, quetiapine and olanzapine and the antidepressant drug mirtazapine in serum was studied by use of a newly developed and validated analytical method based on solid‐phase extraction and liquid chromatography–tandem mass spectrometry. Ascorbic acid was used as an antioxidative agent to stabilize olanzapine during storage and sample preparation. We assessed analyte stability on long‐term storage in serum samples at 25°C, 5°C, −20°C and −80°C, and during five freeze–thaw cycles. Analytes were stable for 23 days at room temperature except for olanzapine and mirtazapine (17 days). All analytes were stable for at least 30 days at 5°C. All analytes were stable for 270 days at −20°C, except for paliperidone and mirtazapine with 60 days and 180 days, respectively. All analytes were stable for 270 days at −80°C. Furthermore, all analytes were stable for five freeze–thaw cycles. We recommend storage at −80°C when samples drawn for analysis of antipsychotic drugs are stored for more than 60 days, whereas a temperature of −20°C is sufficient for storage less than 60 days. [ABSTRACT FROM AUTHOR]

AimThe aim of this study was to study potential cytochrome P450 (CYP) induction by dicloxacillin.MethodsWe performed an open-label, randomized, two-phase, five-drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1 g dicloxacillin three times daily for 10 days. Plasma and urine were collected over 24 h and the concentration of all five drugs and their primary metabolites was determined using a liquid chromatography coupled to triple quadrupole mass spectrometry method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48 h and changes in gene expression and the activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 were investigated. The activation of nuclear receptors by dicloxacillin was assessed using luciferase assays.ResultsA total of 10 days of treatment with dicloxacillin resulted in a clinically and statistically significant reduction in the area under the plasma concentration-time curve from 0 to 24 h for omeprazole (CYP2C19) {geometric mean ratio [GMR] [95% confidence interval (CI)]: 0.33 [0.24, 0.45]}, tolbutamide (CYP2C9) [GMR (95% CI): 0.73 (0.65, 0.81)] and midazolam (CYP3A4) [GMR (95% CI): 0.54 (0.41, 0.72)]. Additionally, other relevant pharmacokinetic parameters were affected, indicating the induction of CYP2C- and CYP3A4-mediated metabolism by dicloxacillin. Investigations in primary hepatocytes showed a statistically significant dose-dependent increase in CYP expression and activity by dicloxacillin, caused by activation of the pregnane X receptor.ConclusionsDicloxacillin is an inducer of CYP2C- and CYP3A-mediated drug metabolism, and we recommend caution when prescribing dicloxacillin to users of drugs with a narrow therapeutic window.

Background: Bone marrow lesions (BMLs) in knee osteoarthritis (OA) have been assessed histopathologically and by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI); however, a direct comparison of the results has not been reported. Purpose: To evaluate and compare the findings by DCE-MRI and histopathology of subchondral BMLs in knee OA. Material and Methods: In total, 19 patients with medial tibiofemoral knee OA undergoing total knee arthroplasty were analyzed. Preoperative MRI, including a DCE sequence, was performed, and bone biopsies were obtained from the resected specimens corresponding to BML areas. The contrast enhancement by DCE-MRI was analyzed using semi-quantitative (area under the curve [AUC]), peak enhancement [PE]), and quantitative (Ktrans, Kep) methods. Enhancement in the medial OA compartment was compared with similar areas in a normal lateral compartment, and the DCE characteristics of BMLs were correlated with semi-quantitatively graded histopathological features. Results: AUC and PE were significantly higher in medial tibial and femoral BMLs compared with the values in the lateral condyles; Ktrans and Kep were only significantly higher in the tibial plateau. In the tibia, AUC and PE were significantly correlated with the grade of vascular proliferation, and PE also with the degree of marrow fibrosis. There was no significant correlation between AUC/PE and histopathological findings in the femur and no correlation between quantitative DCE parameters and histopathological findings. Conclusion: BML characteristics by semi-quantitative DCE in the form of AUC and PE may be used as parameters for the degree of histopathological vascularization in the bone marrow whereas quantitative DCE data were less conclusive. [ABSTRACT FROM AUTHOR]