Evaluation of First-Pass Cytochrome P4503A (CYP3A) and P-glycoprotein Activities Using Felodipine and Hesperetin in Combination in Wistar Rats and Everted Rat Gut Sacs in Vitro

2013 ◽  
Vol 28 (5) ◽  
pp. 699-705 ◽  
Author(s):  
V. Sridhar ◽  
M. Surya Sandeep ◽  
P. Ravindra Babu ◽  
K. Naveen Babu
Keyword(s):  
Wistar Rats ◽  
P Glycoprotein ◽  
First Pass ◽  
Cytochrome P4503a ◽  
Rat Gut

scholarly journals Overexpression of P-glycoprotein, MRP2, and CYP3A4 impairs intestinal absorption of octreotide in rats with portal hypertension

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaoyu Sun ◽  
Shunxiong Tang ◽  
Binbin Hou ◽  
Zhijun Duan ◽  
Zhen Liu ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Western Blot ◽  
In Vitro Experiments ◽  
Rt Pcr ◽  
P Glycoprotein ◽  
Intestinal Microsomes ◽  
First Pass

Abstract Background Portal hypertension (PH) is the main cause of complications and death in liver cirrhosis. The effect of oral administration of octreotide (OCT), a drug that reduces PH by the constriction of mesenteric arteries, is limited by a remarkable intestinal first-pass elimination. Methods The bile duct ligation (BDL) was used in rats to induce liver cirrhosis with PH to examine the kinetics and molecular factors such as P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and cytochrome P450 3A4 (CYP3A4) influencing the intestinal OCT absorption via in situ and in vitro experiments on jejunal segments, transportation experiments on Caco-2 cells and experiments using intestinal microsomes and recombinant human CYP3A4. Moreover, RT-PCR, western blot, and immunohistochemistry were performed. Results Both in situ and in vitro experiments in jejunal segments showed that intestinal OCT absorption in both control and PH rats was largely controlled by P-gp and, to a lesser extent, by MRP2. OCT transport mediated by P-gp and MRP2 was demonstrated on Caco-2 cells. The results of RT-PCR, western blot, and immunohistochemistry suggested that impaired OCT absorption in PH was in part due to the jejunal upregulation of these two transporters. The use of intestinal microsomes and recombinant human CYP3A4 revealed that CYP3A4 metabolized OCT, and its upregulation in PH likely contributed to impaired drug absorption. Conclusions Inhibition of P-gp, MRP2, and CYP3A4 might represent a valid option for decreasing intestinal first-pass effects on orally administered OCT, thereby increasing its bioavailability to alleviate PH in patients with cirrhosis.

scholarly journals Intestinal Absorption Profile of Three Polygala Oligosaccharide Esters in Polygalae Radix and the Effects of Other Components in Polygalae Radix on Their Absorption

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
YinYing Ba ◽  
MengLin Wang ◽  
KunFeng Zhang ◽  
QiJun Chen ◽  
JiaJia Wang ◽  
...  
Keyword(s):  
Future Research ◽  
Active Components ◽  
Sodium Caprate ◽  
P Glycoprotein ◽  
Paracellular Absorption ◽  
Underlying Mechanisms ◽  
The Relationship ◽  
Rat Gut ◽  
Human Nervous System

Oligosaccharide esters, which are among the main active components of Polygalae Radix (PR), demonstrate significant pharmacological activities in the human nervous system. In our previous research, some other constituents in PR were able to improve the bioavailability of oligosaccharide esters such as sibiricose A5 (SA5), sibiricose A6 (SA6), and 3,6′-disinapoyl sucrose (DISS), but the related components and their underlying mechanisms remain unknown. The present study aimed to investigate the intestinal absorptive profile of SA5, SA6, and DISS and the absorptive behavior influenced by the coadministration of polygalaxanthone III and total saponins of PR (TS) using an in vitro everted rat gut sac model, along with the possible mechanisms that may influence absorption. The results showed that TS could significantly enhance the absorption of SA5, SA6, and DISS monomers. Verapamil, a P-glycoprotein inhibitor, was able to elevate the absorption of SA5 and SA6, and an absorption experiment using Rho123 led us to conclude that TS influenced the absorption of SA5 and SA6 in a manner similar to that of a P-glycoprotein inhibitor. Sodium caprate, a paracellular absorption enhancer, was found to increase the absorption of SA5, SA6, and DISS. Results showed that the absorption mechanisms of SA5 and SA6 may combine active transport with paracellular passive penetration, while DISS’s absorption was dominated by paracellular passive penetration. However, the relationship between polygala saponins and the absorption of SA5, SA6, and DISS by paracellular passive penetration remain to be examined. This is the direction of our future research.

Evaluation of First-Pass Cytochrome P4503A (CYP3A) and P-Glycoprotein Activities Using Alfentanil and Fexofenadine in Combination

2005 ◽  
Vol 45 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Evan D. Kharasch ◽  
Alysa Walker ◽  
Christine Hoffer ◽  
Pamela Sheffels
Keyword(s):  
P Glycoprotein ◽  
First Pass ◽  
Cytochrome P4503a

Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacsin vitro

2013 ◽  
Vol 40 (10) ◽  
pp. 1371-1377 ◽  
Author(s):  
M. Surya Sandeep ◽  
V. Sridhar ◽  
Y. Puneeth ◽  
P. Ravindra Babu ◽  
K. Naveen Babu
Keyword(s):  
Oral Bioavailability ◽  
Wistar Rats ◽  
P Glycoprotein ◽  
Rat Gut

scholarly journals In vitro potential modulation of baicalin and baicalein on P-glycoprotein activity and expression in Caco-2 cells and rat gut sacs

2016 ◽  
Vol 54 (9) ◽  
pp. 1548-1556 ◽  
Author(s):  
Qing Miao ◽  
Zhiyong Wang ◽  
Yuanyuan Zhang ◽  
Peipei Miao ◽  
Yuanyuan Zhao ◽  
...  
Keyword(s):  
P Glycoprotein ◽  
Rat Gut

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

Exploring the Pharmacognostic Features, Anti-oxidant and Lipid Lowering Potential of Fagopyrum esculentum Moench. Seed

2020 ◽  
Vol 6 (2) ◽  
pp. 155-169
Author(s):  
Neeraj Panihar ◽  
Neeru Vasudeva ◽  
Sunil Sharma ◽  
Babu Lal Jangir
Keyword(s):  
Ethyl Acetate ◽  
Wistar Rats ◽  
Ethanol Extract ◽  
Water Soluble ◽  
Fagopyrum Esculentum ◽  
Lipid Lowering ◽  
Standard Drug ◽  
Fagopyrum Esculentum Moench ◽  
Β Carotene

Background: Fagopyrum esculentum Moench. is a herb consumed as food and has medicinal value. It is a rich source of bioactive nutrients which cure and prevent many ailments. Traditionally, it is used to treat hypertension, diabetes, constipation, cancer etc. Methods and Objective: Present work illustrates morphological, microscopic and physicochemical parameters of Fagopyrum esculentum seeds as per WHO guidelines, in vitro antioxidant activity; assessed by DPPH scavenging method, hydrogen peroxide scavenging assay and β-carotene linoleic acid bleaching method and study of lipid lowering potential of the ethyl acetate and ethanol extract of seeds on normal diet fed Wistar rats. Results: Morphological studies delineated the triangular shape, dark brown colour, 8 mm length and 6 mm width of the seed. The microscopic examination of the transverse section of seed depicted features like testa or pericarp (seed coat), the endosperm, embryo and sclerenchyma cells. Study of physiochemical parameters exhibited 0.3±0.02% of foreign matter and 1.44±0.51% crude fibre content. Total ash, acid insoluble ash and water soluble ash value were 6.7±1.7%, 1.9±0.23% and 3.9± 0.31% respectively. Alcohol soluble and water soluble extractive value came out to be 65.02± 3.21 mg/g and 12.7±1.24 mg/g respectively. Foaming index was less than 100, swelling index was found to be 0.5±0.01 ml/g. Loss on drying was 4.02±1.27%. Phytochemical screening of ethyl acetate and ethanol extract revealed the presence of alkaloids, carbohydrates, phenolic compounds, phytosterols and flavonoids. Trace amount of heavy metals (arsenic, cadmium, lead, mercury) were determined by atomic absorption spectrophotometer. Pesticide residue analysis confirmed the presence of nontoxic pesticides like dimethipin, hymexazol, phenothrin-2, methoprene, triadimenol, prohydrojasmon- 1, jasmolin ii, triademinol, jasmolin i, prohydrojasmone i, cyromazine in both the extracts by gc-ms spectrometer. The ethyl acetate and ethanol extract has shown significant in-vitro antioxidant activities demonstrated by the DPPH method (IC50 = 94.37±2.51 and 216.04±4.39 μg/ml respectively), hydrogen peroxide scavenging assay (IC50 = 83.72±3.72 and 193.47±5.05 µg/ml respectively) and β-carotene bleaching method (IC50 = 100.67±4.01 and 205.39±2.89 µg/ml respectively). Lipid lowering study performed on Wistar rats demonstrated a significant (p<0.001) decrease in serum Total Cholesterol (TC), Triglyceride (TG) and increase in High Density Lipoprotein (HDL) level as compared to normal group. Both the extracts have shown a non significant difference in the level of TG as compared to standard drug atorvastatin, depicting that the efficacy of extracts is at par with that of standard drug atorvastatin. Conclusion: Pharmacognostical study of the plant can be a very good tool for identification as well as authentication of a herb. Moreover, these parameters may be helpful in the development of monograph of the plant. Pharmacological activity confirmed Fagopyrum esculentum Moench. seed to be a good antioxidant and have lipid lowering potential.

Renal Cortical Slices: An In Vitro Model for Kidney Metabolism and Toxicity

1992 ◽  
Vol 20 (1) ◽  
pp. 71-76
Author(s):  
Andrea Trevisan ◽  
Stefano Maso ◽  
Paola Meneghetti
Keyword(s):  
Wistar Rats ◽  
Reduced Glutathione ◽  
Organic Anion ◽  
Cortical Slice ◽  
Lactate Dehydrogenase Release ◽  
Age Related ◽  
Renal Cortical Slice ◽  
Male Wistar Rats ◽  
Vitro Model

The in vitro renal cortical slice model was used to study: 1) the effects on the kidney of some haloalkanes and haloalkenes using 3-month-old male Wistar rats; 2) influence of age and sex on renal cortical slice indices in non-treated rats; and 3) effects of 1,2-dichloropropane on the slices after pretreatment of 3-month-old male Wistar rats with DL-butathionine-[S,R]-sulphoximine. The most nephrotoxic chemical used was 1,3-dichloropropene, which caused a total depletion in the levels of reduced glutathione, a high peroxidation of lipid (about three thousand-fold with respect to control), a significant release of tubular enzymes into the medium, and loss of organic anion ( p-aminohippurate) accumulation. All the chemicals affected the cytosol more than the brush border. The most remarkable age-related differences in the untreated slices were the progressive decrease of reduced glutathione (p<0.05 from three months of age), and an increase in lactate dehydrogenase release into the medium (p<0.05 from six months of age). By contrast, sex differences were slight. The ‘treatment with 1,2-dichloropropane of slices prepared from rats pretreated with DL-butathionine-[S,R]-sulphoximine significantly increased the depletion of glutathione content (p<0.05) and malondialdehyde release in the medium (p<0.001) caused by the solvent alone.

Insulin-induced endothelin release and vasoreactivity in hypertriglyceridemic and hypertensive rats

1999 ◽  
Vol 277 (1) ◽  
pp. H399-H404 ◽  
Author(s):  
Pilar Nava ◽  
Verónica Guarner ◽  
Rosalinda Posadas ◽  
Israel Pérez ◽  
Guadalupe Baños
Keyword(s):  
Drinking Water ◽  
Receptor Antagonist ◽  
Wistar Rats ◽  
Receptor Blocker ◽  
Hypertensive Rats ◽  
Contractile Responses ◽  
Femoral Arteries ◽  
Male Wistar Rats

Insulin-elicited endothelin release in hypertriglyceridemic, hypertensive, hyperinsulinemic (HTG) rats was shown. Weanling male Wistar rats were given 30% sucrose in their drinking water for 20–24 wk. In vitro contractions of aorta and femoral arteries were elicited with 40 mM KCl. Endothelin release induced with KCl plus 50 μU/ml insulin resulted in increases in contractile responses: 41 ± 5.9 and 57 ± 6% for control and 65.5 ± 6 and 95 ± 9% for HTG aortas and femoral arteries, respectively. The endothelin ETB-receptor blocker BQ-788 decreased responses to KCl + insulin by 39 ± 8 and 53 ± 5% in control and 48 ± 13 and 79 ± 3.5% in HTG aortas and femoral arteries, respectively. The ETA-receptor antagonist PD-151242 inhibited these responses by 12 ± 10 and 1 ± 9% in control and by 51.5 ± 9 and 58.5 ± 1% in HTG aortas and femoral arteries, respectively. These results suggest that endothelin may contribute to the hypertension in this model.

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