Accumulation Of Propranolol Research Articles

Interactive effects of microplastics and selected pharmaceuticals on red tilapia: Role of microplastic aging

The present study used red tilapia (Oreochromis niloticusas) as the model fish to compare the interactive effects between aged and virgin microplastics (MPs) with the antibiotic sulfamethoxazole (SMX) and the β-blocker propranolol (PRP). To this end, the ultraviolet irradiation was used to simulate the MP aging in the environment. The accumulations of MPs and pharmaceuticals, and changes in enzyme activities and genes expressions in tilapia were also evaluated. Some physical properties of MPs changed during the aging process, reflected by 0.27- and 0.16-fold increases in the specific surface area and average pore volume, respectively. And more carbonyl formation was observed on the surface of aged MPs. Compared to the 14-d coexposure with virgin MPs, the MP aging increased the accumulation of PRP by 82.3% in the brain, whereas decreased the concentration of SMX by 46.1% in the gills. The stress on tilapia caused by the MPs and PRP was alleviated by the aging process, largely related to the lower neurotoxicity and reduced lipid peroxidation damages. However, the coexposure to aged MPs and SMX would result in higher inhibitions of cytochrome P450 enzymes activities. The results of the transcriptomics showed that the MP aging mainly influenced the expression of genes related to the metabolic process, immune system process, and the genetic information process in tilapia under the coexposure to MPs and pharmaceuticals. Collectively, our results suggest that the MP aging could induce complex changes in the interactive effects between MPs and pharmaceuticals on aquatic organisms.

Bioaccumulation and biotransformation of the beta-blocker propranolol in multigenerational exposure to Daphnia magna

Multigenerational bioaccumulation and biotransformation activity and short-term kinetics (e.g., uptake and depuration) of propranolol in Daphnia magna were investigated at environmental concentration. The body burden and the major metabolite, desisopropyl propranolol (DIP), of propranolol were quantified using LC-MS/MS at the end of each generation after exposure for 11 generations. The accumulation of propranolol in D. magna at an environmental concentration of 0.2 μg/L was not much different between the parent (F0) and the eleventh filial (F10) generation. However, at 28 μg/L, its accumulation was 1.6 times higher—up to 18.9 μg/g—in the F10 generation relative to the F0. In contrast to propranolol, DIP intensity gradually increased from F0 to F10 at 0.2 μg/L, reflecting an increase in detoxification load and biotransformation performance; no increasing trend was observed at 28 μg/L. The bioaccumulation factor (BAF) showed higher values with a lower concentration and longer period of exposure. The average values of the BAF for 21 days of long-term exposure in successive 11 generations were 440.4 ± 119.7 and 1026.5 ± 208.6 L/kg for 28 μg/L and 0.2 μg/L, respectively. These are comparable to the BAF of 192 for the short-term 72-h exposure at 28 μg/L in the parent generation. It is also recommended that future studies for pharmaceutical ingredients be conducted on drug–drug interaction and structural characteristics on the prediction of biotransformation activity and bioaccumulation rate.

Interactive effects of selected pharmaceutical mixtures on bioaccumulation and biochemical status in crucian carp (Carassius auratus)

The aim of this study was to evaluate the interactive effects of fluoxetine (FLU), roxithromycin (ROX) and propranolol (PRP) on the bioaccumulation and biochemical responses in the crucian carp Carassius auratus. After 7 days of binary exposure (ROX + FLU and PRP + FLU), the addition of waterborne FLU at nominal concentrations of 4, 20 and 100 μg L−1 significantly increased the accumulation of ROX and PRP in fish livers in most cases, although elevated ROX and PRP bioaccumulation levels were not observed in muscles or gills. The inductive response of 7-ethoxyresorufin O-deethylase (EROD) to PRP and that of 7-benzyloxy-4-trifluoromethyl-coumarin O-dibenzyloxylase (BFCOD) to ROX were inhibited by the co-administration of FLU at all tested concentrations. Correspondingly, marked inhibition of CYP1A and CYP3A mRNA expression levels was observed in the livers of fish co-treated with FLU + PRP and FLU + ROX relative to their PRP- and ROX-only counterparts, respectively. In addition, as reflected by superoxide dismutase (SOD) activity and malondialdehyde (MDA) content, co-exposure to ROX + FLU and PRP + FLU seemed to induce stronger antioxidant responses than single pharmaceutical exposure in fish livers. This work indicated that the interactive effects of pharmaceutical mixtures could lead to perturbations in the bioaccumulation and biochemical responses in fish.

Stereoselective Accumulation of Propranolol Enantiomers in K562 and K562/ADR Cells

The stereoselective uptake of propranolol enantiomers was investigated by using the K562 and K562 adriamycin-resistant cell line (K562/ADR) as a model. An enantioselective RP-HPLC method was applied to determine the accumulation of propranolol (PPL) stereoisomers in K562 and K562/ADR cells. The concentration, time and temperature dependent studies showed that the accumulation of S-(-)-PPL was higher than R-(+)-PPL in K562 cells and uptake of R-(+)-PPL was significantly higher than that of S-(-)-PPL in K562/ADR cells. The results indicate the enantioselective accumulation of propranolol enantiomers in K562 and K562 / ADR cells.

Role of prostaglandin E2 and leukotriene B4 in skin reaction induced by transdermal application of propranolol.

Dermal application of propranolol (PRL) induced formation of erythema and edema, and pseudoeosinophil infiltration in epidermis and dermis at the application site in guinea pigs. We investigated the production of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) at the application site of PRL and the role of these inflammatory chemical mediators in the occurrence of the skin reactions. PGE2 was found to be produced at the application site slightly after the accumulation of PRL released from the adhesive bandage in the patch test, and the amount of PGE2 increased continuously, with a peak value obtained at 24 h after application. The time-course changes resembled those of delta a* value, the index of erythema formation determined by colorimetric measurement, and edema formation. The production of PGE2 by dermal application of PRL was suppressed by local pretreatment with dexamethasone or indomethacin. However, no notable production of LTB4 was observed at the application site of PRL.

P-glycoprotein-mediated transport of morphine in brain capillary endothelial cells

Cell accumulation, transendothelial permeability, and efflux studies were conducted in bovine brain capillary endothelial cells (BBCECs) to assess the role of P-glycoprotein (P-gp) in the blood–brain barrier (BBB) transport of morphine in the presence and absence of P-gp inhibitors. Cellular accumulation of morphine and rhodamine 123 was enhanced by the addition of the P-gp inhibitors N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), verapamil, and cyclosporin A. Positive (rhodamine 123) and negative (sucrose and propranolol) controls for P-gp transport also were assessed. Morphine glucuronidation was not detected, and no alterations in the accumulation of propranolol or sucrose were observed. Transendothelial permeability studies of morphine and rhodamine 123 demonstrated vectorial transport. The basolateral to apical (B:A) fluxes of morphine (50 μM) and rhodamine (1 μM) were approximately 50 and 100% higher than the fluxes from the apical to the basolateral direction (A:B), respectively. Decreasing the extracellular concentration of morphine to 0.1 μM resulted in a 120% difference between the B:A and A:B permeabilities. The addition of GF120918 abolished any significant directionality in transport rates across the endothelial cells. Efflux studies showed that the loss of morphine from BBCECs was temperature- and energy-dependent and was reduced in the presence of P-gp inhibitors. These observations indicate that morphine is transported by P-gp out of the brain capillary endothelium and that the BBB permeability of morphine may be altered in the presence of P-gp inhibitors.

Selective lysosomal uptake and accumulation of the beta-adrenergic antagonist propranolol in cultured and isolated cell systems

The beta adrenoreceptor antagonist propranolol is rapidly taken up and accumulated in various cultured cell lines. When incubated in the presence of low concentrations of propranolol (1(T −9M), Hela (non-differentiated epithelia), BC 3H 1 (smooth muscle) and MDCK (differentiated kidney epithelia) cell cultures take up ( t 1/2 = 4–10 min) and accumulate the drug such that the intracellular concentration is over 1000 times that in the incubation medium. The release of propranolol from the cells was slower ( t 1 2 = 22 min ) than the rate of uptake but the dissociation was stimulated by the addition of 1 μM propranolol to the external medium ( t 1 2 = 9 min). Uptake, which is non-stereoselective, is dependent on pH and is inhibited by the lysosomotropic agents, NH 4Cl, methylamine and chloroquine. At higher concentrations (>10 6M), uptake is accompanied by a visual swelling of intracellular acidic vesicles staining with acridine orange. These results suggest that propranolol, a basic amphiphilic amine. is accumulated within the lysosomes of these cells. Uptake was confined to these cultured cell systems with no chloroquine-sensitive propranolol uptake, being found in isolated rabbit ventricular myocytes, red blood cells or blood platelets. Although alprenolol and cyanopindolol competed with propranolol for uptake, isoprenaline, adrenaline, noradrenaline, phenylephrine, atenolol, practolol and salbutamol were not effective inhibitors. The possible consequences of this uptake and accumulation of propranolol by certain tissues is discussed in relation to the known actions of the drug, particularly during or after abrupt withdrawal from chronic applications.

Direct measurement of propranolol bioavailability during accumulation to steady-state.

1. A high performance liquid chromatographic method for the determination of propranolol in human plasma and blood has been developed and used to confirm that cumulation occurred during chronic oral administration, steady-state being achieved within 48 h of beginning 80 mg of the drug every 8 h. 2. The method was adapted to measure [H3]-propranolol and native drug in the same blood sample and was applied to determine simultaneously the disposition of i.v. ([H3]-propranolol) and orally (non-labelled) administered drug after single oral dose of 80 mg and when steady-state had been established on an 80 mg, 8-hourly regimen. 3. Using this approach it was possible to show that a reduced oral clearance at steady-state was associated with a smaller reduction in systemic (i.v.) clearance and no change in liver blood flow. A direct estimate of bioavailability was also possible and was found to be increased at steady-state compared with a single oral dose. 4. We conclude that the accumulation of propranolol during the attainment of steady-state is due to a reduction in intrinsic clearance, resulting in reduced presystemic hepatic extraction.