0
selected
-
1.
Optimization of a drug transporter probe cocktail: potential screening tool for transporter-mediated drug-drug interactions.
Stopfer, P, Giessmann, T, Hohl, K, Hutzel, S, Schmidt, S, Gansser, D, Ishiguro, N, Taub, ME, Sharma, A, Ebner, T, et al
British journal of clinical pharmacology. 2018;(9):1941-1949
-
-
Free full text
-
Abstract
AIMS: Previous pharmacokinetic characterization of a transporter probe cocktail containing digoxin (P-gp), furosemide (OAT1, OAT3), metformin (OCT2, MATE1, MATE2-K) and rosuvastatin (OATP1B1, OATP1B3, BCRP) in healthy subjects showed increases in rosuvastatin systemic exposure compared to rosuvastatin alone. In this trial, the doses of metformin and furosemide as putative perpetrators were reduced to eliminate their drug-drug interaction (DDI) with rosuvastatin. METHODS In a randomized, open-label, single-centre, five-treatment, five-period crossover trial, 30 healthy male subjects received as reference treatments separately 0.25 mg digoxin, 1 mg furosemide, 10 mg metformin and 10 mg rosuvastatin, and as test treatment all four drugs administered together as a cocktail. Primary pharmacokinetic endpoints were AUC0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration) and Cmax (maximum plasma concentration) of each probe drug. RESULTS Geometric mean ratios and 90% confidence intervals of test (cocktail) to reference (single drug) for AUC0-tz were 96.4% (88.2-105.3%) for digoxin, 102.6% (93.8-112.3%) for furosemide, 97.5% (93.5-101.6%) for metformin and 105.0% (96.4-114.4%) for rosuvastatin, indicating lack of interaction. The same analysis for Cmax and for pharmacokinetic parameters of urinary excretion of all cocktail components also indicated no DDI. CONCLUSIONS Digoxin (0.25 mg), furosemide (1 mg), metformin (10 mg) and rosuvastatin (10 mg) exhibit no mutual pharmacokinetic interactions and are well tolerated administered as a cocktail. The cocktail is thus optimized and has the potential to be used as a screening tool for clinical investigation of transporter-mediated DDI.
-
2.
Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters.
Katsube, T, Miyazaki, S, Narukawa, Y, Hernandez-Illas, M, Wajima, T
European journal of clinical pharmacology. 2018;(7):931-938
Abstract
PURPOSE Cefiderocol, a siderophore cephalosporin, will be used concomitantly with other medications for treatment of bacterial infections. In vitro studies demonstrated inhibition potential of cefiderocol on organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 2-K, and organic anion transporting polypeptide (OATP) 1B3. The aim of this study was to assess in vivo drug-drug interaction (DDI) potential of cefiderocol using probe substrates for these transporters. METHODS DDI potentials of cefiderocol as inhibitors were assessed in a clinical study consisting of 3 cohorts. Twelve or 13 healthy adult subjects per cohort orally received a single dose of furosemide 20 mg (for OAT1/3), metformin 1000 mg (for OCT1/2 and MATE2-K), or rosuvastatin 10 mg (for OATP1B3) with or without co-administration with cefiderocol 2 g every 8 h with 3-h infusion (a total of 3, 6, and 9 doses of cefiderocol with furosemide, metformin, and rosuvastatin, respectively). DDI potentials were assessed based on the pharmacokinetics of the substrates. RESULTS Ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve were 1.00 (0.71-1.42) and 0.92 (0.73-1.16) for furosemide, 1.09 (0.92-1.28) and 1.03 (0.93-1.15) for metformin, and 1.28 (1.12-1.46) and 1.21 (1.08-1.35) for rosuvastatin, respectively. Exposures to furosemide or metformin did not change when co-administered with cefiderocol. Slight increase in rosuvastatin exposure was observed with co-administered with cefiderocol, which was not considered to be clinically significant. Each treatment was well tolerated. CONCLUSIONS Cefiderocol has no clinically significant DDI potential via drug transporters.
-
3.
Impact of a cholesterol membrane transporter's inhibition on vitamin D absorption: A double-blind randomized placebo-controlled study.
Silva, MC, Faulhauber, GAM, Leite, ÉN, Goulart, KR, Ramirez, JMA, Cocolichio, FM, Furlanetto, TW
Bone. 2015;:338-342
Abstract
Oral supplements are important to prevent and treat vitamin D deficiency. Despite the growing number of prescriptions, vitamin D's absorptive mechanisms are not clearly elucidated. By evaluating the effect of ezetimibe on vitamin D absorption, we aim to determine if the cholesterol transporter Niemann-Pick C1-Like 1 transporter contributes to it. This randomized, double-blind, placebo-controlled trial (ClinicalTrials.govNCT02234544) was developed in a South Brazilian University Hospital. Fifty-one medical students were randomized to ezetimibe 10mg/day or placebo for 5 days. On the fifth and 19th days, blood samples for 25-hydroxycholecalciferol (25OHD), parathyroid hormone (PTH), calcium, and albumin were collected. After the first blood sample collection, all participants received a single oral 50,000 IU cholecalciferol dose during a 15 g-fat meal. Serum 25OHD levels were measured by the immunoassay Diasorin Liaison®. Measurements were compared in a general linear model adjusted for multiple comparisons by the Bonferroni test. Before cholecalciferol administration, 25OHD was <30 ng/mL and <20 ng/mL, respectively, in all and in 82.3% of the participants. Fourteen days after a single 50,000 IU oral dose of cholecalciferol, mean (SD) changes in serum 25OHD were similar in both groups, after adjustment to BMI and 25OHD levels before cholecalciferol administration (p=0.26): 8.7 (3.7) ng/mL in the ezetimibe group, versus 10.0 (3.8) ng/mL in the placebo group. Mean serum 25OHD, PTH, calcium and albumin levels remained similar in both groups. We conclude that ezetimibe had no effect on the mean change in serum 25OHD after a single oral dose of cholecalciferol, in these healthy and young adults.
-
4.
Importance of pH regulation and lactate/H+ transport capacity for work production during supramaximal exercise in humans.
Messonnier, L, Kristensen, M, Juel, C, Denis, C
Journal of applied physiology (Bethesda, Md. : 1985). 2007;(5):1936-44
Abstract
We examine the influence of the cytosolic and membrane-bound contents of carbonic anhydrase (CA; CAII, CAIII, CAIV, and CAXIV) and the muscle content of proteins involved in lactate and proton transport [monocarboxylate transporter (MCT) 1, MCT4, and Na(+)/H(+) exchanger 1 (NHE1)] on work capacity during supramaximal exercise. Eight healthy, sedentary subjects performed exercises at 120% of the work rate corresponding to maximal oxygen uptake (W(max)) until exhaustion in placebo (Con) and metabolic alkalosis (Alk) conditions. The total (W(tot)) and supramaximal work performed (W(sup)) was measured. Muscle biopsies were obtained before and immediately after standardized exercises (se) at 120% W(max) in both conditions to determine the content of the targeted proteins, the decrease in muscle pH (DeltapH(m)), and the muscle lactate accumulation ([Lac](m)) per joule of W(sup) (DeltapH(m)/W(sup-se) and Delta[Lac](m)/W(sup-se), respectively) and the dynamic buffer capacity. In Con, W(sup) was positively [corrected] correlated with [corrected] MCT1, and tended to be positively correlated with MCT4 and NHE1. CAII + CAIII were correlated positively with DeltapH(m)/W(sup-se) and negatively with Delta[Lac](m)/W(sup-se), while CAIV was positively related to W(tot). The changes in W(sup) with Alk were correlated positively with those in dynamic buffer capacity and negatively with W(sup) in Con. Performance improvement with Alk was greater in subjects having a low content of proteins involved in pH regulation and lactate/proton transport. These results show the importance of pH regulating mechanisms and lactate/proton transport on work capacity and the role of the CA to delay decrease in pH(m) and accumulation in [Lac](m) during supramaximal exercise in humans.
-
5.
Reversed diurnal variation in depression: associations with a differential antidepressant response, tryptophan: large neutral amino acid ratio and serotonin transporter polymorphisms.
Joyce, PR, Porter, RJ, Mulder, RT, Luty, SE, McKenzie, JM, Miller, AL, Kennedy, MA
Psychological medicine. 2005;(4):511-7
Abstract
BACKGROUND Although diurnal variation of mood is a widely recognized symptom of depression, the clinical, neurobiological and psychopharmacological significance of this symptom has not previously been reported. METHOD A total of 195 depressed out-patients underwent a detailed clinical and neurobiological assessment, and were then randomized to treatment with either fluoxetine or nortriptyline. RESULTS Of the 195 depressed patients, 62 had a pattern of reversed diurnal variation (i.e. worse in the evening). Those with reversed diurnal variation had a poorer response to a serotonergic anti-depressant, were less likely to have bipolar II disorder, had a higher tryptophan: large neutral amino acid ratio and had different allele frequencies of the polymorphisms in the promoter region of the serotonin transporter. CONCLUSIONS These findings raise the possibility of serotonergic influence on diurnal variation, and that the symptom of reversed diurnal variation is of relevance to antidepressant prescribing.
-
6.
Validation of [(123)I]beta-CIT SPECT to assess serotonin transporters in vivo in humans: a double-blind, placebo-controlled, crossover study with the selective serotonin reuptake inhibitor citalopram.
de Win, MM, Habraken, JB, Reneman, L, van den Brink, W, den Heeten, GJ, Booij, J
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2005;(5):996-1005
Abstract
Disturbances in the serotonin (5-HT) system are associated with various neuropsychiatric disorders. The 5-HT system can be studied in vivo by measuring 5-HT transporter (SERT) densities using (123)iodine-labeled 2beta-carbomethoxy-3beta(4-iodophenyl)tropane ([(123)I]beta-CIT) and single photon emission computed tomography (SPECT). Validation of this technique is important because [(123)I]beta-CIT does not bind selectively to SERTs. Some studies have validated this technique in vivo in the human brain in SERT-rich areas, but the technique has not been validated yet in SERT-low cortical areas. The aim of this study was to further validate [(123)I]beta-CIT SPECT in assessing SERTs in vivo in humans in both SERT-rich and SERT-low areas. A double-blind, placebo-controlled, crossover design was used with the selective 5-HT reuptake inhibitor (SSRI) citalopram. Six male subjects underwent two [(123)I]beta-CIT SPECT sessions: one after pretreatment with citalopram and one after placebo. Scans were acquired 4 h and 22-27 h p.i., and both region-of-interest and voxel-by-voxel analyses were performed. Citalopram reduced [(123)I]beta-CIT binding ratios in SERT-rich midbrain and (hypo)thalamus. Binding ratios were also lower after citalopram in SERT-low cortical areas, but statistical significance was only reached in several cortical areas using voxel-by-voxel analysis. In addition, citalopram increased binding ratios in the DAT-rich striatum and increased absolute uptake in the cerebellum. The results show that [(123)I]beta-CIT SPECT is a valid technique to study SERT binding in vivo in human brain in SERT-rich areas. Although we provide some evidence that [(123)I]beta-CIT SPECT may be used to measure SERTs in SERT-low cortical areas, these measurements must be interpreted with caution.
-
7.
Dopamine transporter gene polymorphism, spect imaging, and levodopa response in patients with Parkinson disease.
Contin, M, Martinelli, P, Mochi, M, Albani, F, Riva, R, Scaglione, C, Dondi, M, Fanti, S, Pettinato, C, Baruzzi, A
Clinical neuropharmacology. 2004;(3):111-5
Abstract
OBJECTIVES To assess the potential association between dopamine transporter (DAT) genotype, single photon emission CT (SPECT) measures using [123I]-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane ([123I]-FP-CIT) of striatal dopaminergic function, and oral levodopa response pattern in a cohort of patients with Parkinson disease. METHODS Thirty-six patients at different disease stages enrolled in the study. Each patient was examined by [123I]-FP-CIT SPECT and a standardized oral levodopa test on 2 separate days in a randomized order within 3 weeks. The main outcome variables were the specific-to-nonspecific tracer uptake ratio in the contralateral putamen for SPECT analysis; latency, duration, and magnitude of the motor effect; and presence of dyskinesias for the levodopa test. The variable number of tandem repeat (VNTR) polymorphisms of the gene coding for DAT were detected for each patient by standard methods. RESULTS Contralateral putamen [123I]-FP-CIT uptake ratios were similar in the patients carrying the 9-copy allele (n=20) of the DAT VNTR compared with 10-repeat homozygotes (n=16). No significant difference was found in levodopa main outcome variables and dyskinesia incidence between the two groups of patients stratified by DAT VNTR polymorphism. CONCLUSIONS The study did not identify clinically relevant in vivo DAT neurochemical function phenotypes or levodopa response patterns associated with the DAT polymorphism.