scholarly journals Inhibition of Human Efflux Transporter ABCC2 (MRP2) by Self-emulsifying Drug Delivery System: Influences of Concentration and Combination of Excipients

2014 ◽  
Vol 17 (4) ◽  
pp. 447 ◽  
Author(s):  
Liang Li ◽  
Tao Yi ◽  
Christopher Wai-kei Lam
Keyword(s):  
Drug Delivery ◽  
Atpase Activity ◽  
Cell Model ◽  
Ultra Performance Liquid Chromatography ◽  
Inhibitory Effect ◽  
Combined Effects ◽  
Efflux Transporter ◽  
Peg 400 ◽  
Efflux Ratio ◽  
Liquid Chromatography Tandem Mass

PURPOSE: This study investigated influences of concentration and combination of excipients, commonly used in self-emulsifying drug delivery systems (SEDDS), on inhibition of human efflux transporter ABCC2 (MRP2). METHODS: Ten commonly used excipients of SEDDS with inhibitory effect on MRP2 including Cremophor® EL, Cremophor® RH, Pluronic® F127, Maisine® 35-1, β-cyclodextrin, Labrasol®, Pluronic® F68, PEG 2000, PEG 400 and Transcutol® were studied with the Caco-2 cell model. Six excipients with inhibitory effect including Cremophor® EL, Cremophor® RH, Pluronic® F127, PEG 2000, PEG 400 and Transcutol® were further analyzed using the MRP2 vesicle assay and ATPase activity assay. Ultra-performance liquid-chromatography tandem mass spectrometry was used to measure scutellarin as the MRP2 substrate. RESULTS: In studying concentration-dependent effects, five excipients including Cremophor® EL, Cremophor® RH, Pluronic® F127, Maisine® 35-1 and β-cyclodextrin showed concentration-dependent decrease in efflux ratio of scutellarin. The other five excipients did not show such phenomenon, and their inhibitory effects were restricted to be above to certain critical or minimum concentrations. In studying combined effects, PEG 2000 and Pluronic® F127 both showed combined effect with Cremophor® EL on inhibiting MRP2. However, some combinations of excipients such as PEG 400　and Transcutol® with Cremophor® EL increased the scutellarin efflux ratio and decreased the transport of scutellarin and ATPase activity, compared to Cremophor® EL alone. CONCLUSION: The above results suggest that appropriate choice of excipients according to their concentration-dependent and combined effects on MRP2 inhibition can facilitate formulation of SEDDS for improving the bioavailability of drugs that are MRP2 substrates. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Cardiac sarcolemmal Na+-K+-ATPase: combined effects of propranolol and arachidonyl CoA

1983 ◽  
Vol 244 (5) ◽  
pp. H738-H742
Author(s):  
J. H. Kramer ◽  
K. Owens ◽  
W. B. Weglicki
Keyword(s):  
Atpase Activity ◽  
Cardiac Myocytes ◽  
Inhibitory Effect ◽  
Fatty Acyl ◽  
Combined Effects ◽  
No Inhibition

Sarcolemma from adult canine cardiac myocytes (Na+-K+-ATPase activity 71.8 +/- 3.4 mumol . mg protein-1 . h-1) was preincubated (10 min at 37 degrees C, pH 7.2) with 1) 5-250 microM arachidonyl CoA, 2) 2.5 nM- 2.5 mM propranolol, 3) 5-250 microM arachidonyl CoA plus 2.5 mM propranolol or 4) 2.5 nM-2.5 mM propranolol plus 50 microM arachidonyl CoA; after preincubation the Na+-stimulatable activity was assayed. Arachidonyl CoA alone (50 microM, expt 1) elicited maximum stimulation (89% above control), whereas concentrations greater than 125 microM were inhibitory. Preincubation with propranolol alone (expt 2) had no significant effect on activity. However, when membranes were pretreated with both arachidonyl CoA and 2.5 mM propranolol (expt 3) activity was significantly inhibited. Preincubation with concentrations of propranolol greater than 25 microM were required to reverse the stimulatory effect of 50 microM arachidonyl CoA (expt 4). Propranolol and arachidonyl CoA do not have to be present simultaneously to produce an inhibitory effect. Activity was greatly inhibited (87%) when membranes were preincubated with 100 microM arachidonyl CoA followed by addition of 2.5 mM propranolol; no inhibition was observed if preincubation conditions were reversed. These data suggest that propranolol-induced inhibition of the Na+-K+-ATPase is reversible but becomes irreversible when sarcolemma is pretreated with the fatty acyl CoA, either prior to or during propranolol preincubation.

scholarly journals Effect of Paclobutrazol on the Physiology and Biochemistry of Ophiopogon japonicus

Agronomy ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1533
Author(s):  
Zezhou Zhang ◽  
Ruixing Li ◽  
Deyong Chen ◽  
Jieyin Chen ◽  
Ouli Xiao ◽  
...  
Keyword(s):  
Ultra Performance Liquid Chromatography ◽  
Inhibitory Effect ◽  
Plant Sample ◽  
Root Weight ◽  
Residual Concentration ◽  
Transmission Electron ◽  
Ophiopogon Japonicus ◽  
Physiology And Biochemistry ◽  
Liquid Chromatography Tandem Mass ◽  
Tuber Root

Ophiopogon japonicus is a commonly used Chinese medicine with multiple pharmacological effects. To increase the yield of O. japonicus, paclobutrazol is widely used during the cultivation, and residues of paclobutrazol cause undesired side effects of O. japonicus. In this study, the effect of different concentrations of paclobutrazol on O. japonicus was investigated, and the final residual amount of paclobutrazol in the plant sample was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS); cell morphology was observed by transmission electron microscopy. The inhibitory effect of paclobutrazol on plant height and the stimulatory effect on root elongation were concentration-dependent from 0.6 to 11.3 g/L, reaching a maximum of about 28% and 67%, respectively. However, when the concentration was 22.5 g/L, these effects were significantly weakened, and the same trend was observed for the tuber root weight. Paclobutrazol caused the cell wall of O. japonicus to thicken, making the cells smaller and more densely arranged. Paclobutrazol also inhibited bacterial growth, irrespective of the concentration. Considering the residual concentration after application and the effects on growth, the application of 1.3 g/L or 2.8 g/L paclobutrazol can increase the accumulation of effective ingredients while promoting production, reducing application costs, and maximizing farmers’ profit.

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