The present investigation demonstrates that NO, but not prostacyclin, is essential for flow-mediated dilatation of large human arteries. Hence, this response can be used as a test for the L-arginine/NO pathway in clinical studies.

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One in 11 primary care patients had frequent difficulties in swallowing tablets and capsules while GPs grossly underestimated these problems. Therefore, physicians should rule out swallowing difficulties regularly to avoid non-adherence and inappropriate drug modifications. Special attention should be paid to specific patient groups (e.g. women and patients with dysphagia, dysphagia indicators, or mental illness).

Pharmacokinetic drug-drug interactions often occur at the level of P-glycoprotein (Pgp). To study possible interactions caused by the newer antidepressants we investigated citalopram, fluoxetine, fluvoxamine, paroxetine, reboxetine, sertraline, and venlafaxine and their major metabolites desmethylcitalopram, norfluoxetine, paroxetine-metabolite (paroxetine-M), desmethylsertraline, N-desmethylvenlafaxine, and O-desmethylvenlafaxine for their ability to inhibit Pgp. Pgp inhibition was studied by a fluorometric assay using calcein-acetoxymethylester as Pgp substrate and two different cell systems: L-MDR1 cells (model for human Pgp) and primary porcine brain capillary endothelial cells (pBCECs, model for the blood-brain barrier). Both cell systems proved to be suitable for the evaluation of Pgp inhibitory potency of drugs. All antidepressants tested except O-desmethylvenlafaxine showed Pgp inhibitory activity with sertraline, desmethylsertraline, and paroxetine being the most potent, comparable with the well known Pgp inhibitor quinidine. In L-MDR1 cells fluoxetine, norfluoxetine, fluvoxamine, reboxetine, and paroxetine-M revealed intermediate Pgp inhibition and citalopram, desmethylcitalopram, venlafaxine, and N-desmethylvenlafaxine were only weak inhibitors. The ranking order was similar in pBCECs. The fact that some of the compounds tested exert Pgp inhibitor effects at similar concentrations as quinidine suggests that pharmacokinetic drugdrug interactions between the newer antidepressants and Pgp substrates should now be thoroughly studied in vivo.P-glycoprotein (Pgp) is a member of the ATP-binding cassette superfamily of membrane transport proteins, responsible for the efflux of many drugs. It represents a major component of the blood-brain barrier (Schinkel et al., 1994) and the intestinal barrier (van Asperen et al., 1998), and it contributes to renal and biliary elimination of drugs (Kusuhara et al., 1998;Chiou et al., 2000). At the blood-brain barrier Pgp is localized in the apical membrane of brain capillary endothelial cells and transports substrates toward the blood compartment (Cordon-Cardo et al., 1989;van Asperen et al., 1997). Therefore, Pgp can limit the penetration into and retention within the brain and thus modulate effectiveness and central nervous system toxicity of numerous compounds. In contrast, the absence of active Pgp as observed in mdr-1 knockout mice lacking Pgp and thus exhibiting unrestricted access of Pgp substrates to the brain yields significantly increased central nervous system concentrations often exceeding those observed in wild-type mice by orders of magnitude (Schinkel et al., 1994(Schinkel et al., , 1996. Pgp is also highly expressed in the apical membrane of epithelial cells in the small and large intestine, where it transports drugs out of the cells into the intestinal lumen (Cordon-Cardo et al., 1989;van Asperen et al., 1998), thus limiting bioavailability of compounds such as paclitaxel and human immunodeficiency virus protease inhibitors (Sparreboom et al., 1997...

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Pharmacokinetic variability of voriconazole is largely caused by CYP3A4-and CYP2C19-mediated metabolism.• Oral bioavailability of voriconazole has been claimed to be almost 100%, thus facilitating a change from intravenous to oral application without dose adjustment. WHAT THIS STUDY ADDS• For the first time voriconazole exposure after intravenous and oral administration in relation to CYP2C19 activity is reported.• In addition, the predominant metabolic pathway is the hydroxylation that seems to be influenced by the CYP2C19 genotype.• Enterohepatic circulation of both hydroxylated metabolites must be anticipated. AIMSThe aim was to determine the pharmacokinetics of voriconazole after a single oral dose in comparison with intravenous (i.v.) administration in healthy individuals stratified according to the cytochrome P450 (CYP) 2C19 genotype. In addition, the possible metabolic pathways and their modulation according to CYP2C19 genotype were investigated after oral and i.v. administration of voriconazole. METHODSIn a single-centre, open-label, two-period crossover study 20 participants received single doses of 400 mg voriconazole orally and 400 mg voriconazole intravenously in randomized order. Blood and urine samples were collected up to 96 h post dose and the voriconazole and three major metabolites were quantified by high-performance liquid chromatography coupled to mass spectroscopy. RESULTSAbsolute oral bioavailability of voriconazole was 82.6% (74.1, 91.0). It ranged from 94.4% (78.8, 109.9) in CYP2C19 poor metabolizers to 75.2% (62.9, 87.4) in extensive metabolizers. In contrast to voriconazole and its N-oxide, the plasma concentrations of both hydroxylated metabolites showed a large second peak after 24 h. Independent of the route of administration, voriconazole partial metabolic hydroxylation after i.v. administration was eightfold higher compared with N-oxidation [48.8 ml min -1 (30.5, 67.1) vs. 6.1 ml min -1 (4.1, 8.0)]. The formation of the metabolites was related to CYP2C19 activity. CONCLUSIONSIndependent of the route of administration, voriconazole exposure was three times higher in CYP2C19 poor metabolizers compared with extensive metabolizers. Voriconazole has a high bioavailability with no large differences between the CYP2C19 genotypes. The hydroxylation pathway of voriconazole elimination exceeded the N-oxidation, both influenced by the CYP2C19 genotype.

In vitro data on the metabolism of the antifungal voriconazole suggest that its pharmacokinetics might be influenced by the activity of CYP2C19, CYP2C9, and CYP3A. To elucidate the genetic influence of polymorphic enzymes on voriconazole metabolism, the authors pooled the pharmacokinetic data from 2 interaction studies in which 35 participants were enrolled according to their CYP2C19 genotype to receive a single 400-mg oral dose of voriconazole. Nine participants were homozygous for CYP2C19(*)1/(*)1, 8 heterozygous for (*)1/(*)17, 11 heterozygous for (*)1/(*)2, 2 heterozygous for (*)2/(*)17, 4 homozygous for (*)2/(*)2, and 1 with a double mutation CYP2C19(*)2/(*)2(*)17. Nine (heterozygous) individuals were carriers of the CYP2C9(*)2 or (*)3 variant alleles. Twenty-five participants did not express the CYP3A5 isozyme ((*)3/(*)3), whereas in 5 individuals, the (*)1/(*)3 combination was present (active enzyme). In addition, the CYP2D6 genotype and 2 variants of the drug transporter MDR1 (C3435T and G2677T) were determined. Multiple regression analysis of voriconazole apparent oral clearance revealed that 49% of its variance can be explained solely by the CYP2C19 polymorphism (P < .0001). Including the other polymorphisms into the regression model did not show any significant contribution. The number of variant CYP2C19 alleles therefore explains a substantial part of the wide variability of voriconazole pharmacokinetics, whereas the presence of functional CYP3A5 and the CYP2C9 genotype had no significant impact on voriconazole exposure. Some minor contribution results from the MDR1 C3435T genotype.

BackgroundThe concept of frailty is rapidly gaining attention as an independent syndrome with high prevalence in older adults. Thereby, frailty is often related to certain adverse outcomes like mortality or disability. Another adverse outcome discussed is increased health care utilization. However, only few studies examined the impact of frailty on health care utilization and corresponding costs. The aim of this study was therefore to investigate comprehensively the relationship between frailty, health care utilization and costs.MethodsCross sectional data from 2598 older participants (57–84 years) recruited in the Saarland, Germany, between 2008 and 2010 was used. Participants passed geriatric assessments that included Fried’s five frailty criteria: weakness, slowness, exhaustion, unintentional weight loss, and physical inactivity. Health care utilization was recorded in the sectors of inpatient treatment, outpatient treatment, pharmaceuticals, and nursing care.ResultsPrevalence of frailty (≥3 symptoms) was 8.0 %. Mean total 3-month costs of frail participants were €3659 (4 or 5 symptoms) and €1616 (3 symptoms) as compared to €642 of nonfrail participants (no symptom). Controlling for comorbidity and general socio-demographic characteristics in multiple regression models, the difference in total costs between frail and non-frail participants still amounted to €1917; p < .05 (4 or 5 symptoms) and €680; p < .05 (3 symptoms). Among the 5 symptoms of frailty, weight loss and exhaustion were significantly associated with total costs after controlling for comorbidity.ConclusionsThe study provides evidence that frailty is associated with increased health care costs. The analyses furthermore indicate that frailty is an important factor for health care costs independent from pure age and comorbidity. Costs were rather attributable to frailty (and comorbidity) than to age. This stresses that the overlapping concepts of multimorbidity and frailty are both necessary to explain health care use and corresponding costs among older adults.Electronic supplementary materialThe online version of this article (doi:10.1186/s12913-016-1360-3) contains supplementary material, which is available to authorized users.