scholarly journals Recapitulation of First Pass Metabolism Using 3D Printed Microfluidic Chip and Organoid

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3301
Author(s):  
Bo-Eun Lee ◽  
Do-Kyung Kim ◽  
Hyunil Lee ◽  
Siyeong Yoon ◽  
Sin-Hyung Park ◽  
...  
Keyword(s):  
Microfluidic Chip ◽  
Computer Aided Design ◽  
Colorectal Adenocarcinoma ◽  
Low Cost ◽  
Drug Efficacy ◽  
Gradient Force ◽  
First Pass Metabolism ◽  
First Pass ◽  
Pass Metabolism

The low bioavailability of oral drugs due to first pass metabolism is a major obstacle in drug development. With significant developments in the field of in vitro organ modeling and microfluidic chip three-dimensional (3D) printing, the challenge is to apply these for the production and evaluation of new drug candidates. This study aimed to produce a microfluidic chip to recapitulate and assess the feasibility of the first pass metabolism. The infill condition of the polycarbonate transparent filament and layer height was optimized to visualize and maintain the organoid or spheroid on the chip. Next, the chip was fabricated using a 3D printer after a computer-aided design (CAD). The chip consisted of three wells of different heights. The small intestinal (SI) organoid and colorectal adenocarcinoma spheroids were placed on the second and third wells, respectively. No additional equipment was assembled, and the tilted tunnel was connected to each well to transport the material by gradient force. The chip was fabricated using 50% and 0.1 um thickness. Among the three different prototypes of chip (chips 1, 2, and 3), the highest distribution of plasmids in the Matrigel of the second well was observed in Chip 2 at 48 h. The effect of first pass metabolism was analyzed using docetaxel. In the chip without an SI organoid, there was a marked decrease in the viability of colorectal adenocarcinoma spheroids due to drug efficacy. However, in the chip with the SI organoid, no significant change in viability was observed because of first pass metabolism. In conclusion, we presented a simple, fast, and low-cost microfluidic chip to analyze the efficacy change of candidate drug by the first pass metabolism.

Formulation and Characterization of Eplerenone Mucoadhesive Buccal Tablets

2021 ◽  
pp. 3097-3103
Author(s):  
Harini Amballa ◽  
Navaneetha Kaluva ◽  
Sree Giri Prasad Beri ◽  
Krishna Mohan Chinnala ◽  
Mayuri Konda
Keyword(s):  
Drug Delivery ◽  
Drug Release ◽  
Drug Delivery System ◽  
Delivery System ◽  
Release System ◽  
First Pass Metabolism ◽  
First Pass ◽  
Buccal Tablets ◽  
Pass Metabolism

Mucoadhesive drug release system is a preferably unidirectional release system where mucosal epithelial exterior is enclosed by the mucus deposit that interacts with the bio-adhesive drug delivery system and swelling time of the buccal dosage form which is amplified by mucin molecules at the location of administration. Eplerenone is an Anti-hypertensive drug that undergoes hepatic first pass metabolism and shows 69% of bioavailability. In order to bypass the hepatic first pass metabolism the drug is designed to be delivered through buccal cavity to avoid the first pass metabolism. Eplerenone buccal tablets were formulated by using direct compression method with different polymers like HPMC K 100M, Carbopol 934P, Carbopol 974P, Xantham Gum, Eudragit L100 and NaCMC in various concentrations and compositions. Incompatibility complications were not observed from the FTIR spectrums. The formulated and prepared buccal solid dosage forms were evaluated for pre-compressions and post- compression parameters such as hardness, weight variation, thickness, friability, surface pH, swelling index, in-vitro dissolution studies, drug content uniformity, mucoadhesion strength and mucoadhesion time. Evaluation results of formulation F12 are proven to be the optimal formulation showing highest mucoadhesion time, mucoadhesion strength and in-vitro drug release for prolonged period of time about 8 hours. Eplerenone is best delivered through buccal drug delivery system to enhance its oral bioavailability and bypass the hepatic first pass metabolism.

scholarly journals Predicting Intestinal and Hepatic First-Pass Metabolism of Orally Administered Testosterone Undecanoate

2020 ◽  
Vol 10 (20) ◽  
pp. 7283 ◽  
Author(s):  
Atheer Zgair ◽  
Yousaf Dawood ◽  
Suhaib M. Ibrahem ◽  
Hyun-moon Back ◽  
Leonid Kagan ◽  
...  
Keyword(s):  
Liver Microsomes ◽  
Hepatic Metabolism ◽  
Hydrolysis Time ◽  
Testosterone Undecanoate ◽  
Main Site ◽  
Cell Homogenate ◽  
First Pass Metabolism ◽  
First Pass ◽  
Pass Metabolism

The bioavailability of orally administered drugs could be impacted by intestinal and hepatic first-pass metabolism. Testosterone undecanoate (TU), an orally administered ester prodrug of testosterone, is significantly subjected to first-pass metabolism. However, the individual contribution of intestinal and hepatic first-pass metabolism is not well determined. Therefore, the aim of the current study was to predict the metabolic contribution of each site. The hydrolysis–time profiles of TU incubation in human liver microsomes and Caco-2 cell homogenate were used to predict hepatic and intestinal first-pass metabolism, respectively. The in vitro half-life (t1/2 inv) for the hydrolysis of TU in microsomal mixtures was 28.31 ± 3.51 min. By applying the “well-stirred” model, the fraction of TU that could escape hepatic first-pass metabolism (FH) was predicted as 0.915 ± 0.009. The incubation of TU in Caco-2 cell homogenate yielded t1/2 inv of 109.28 ± 21.42 min, which was applied in a “Q gut” model to estimate the fraction of TU that would escape intestinal first-pass metabolism (FG) as 0.114 ± 0.02. Accordingly, only 11% of the absorbed fraction of TU could escape intestinal metabolism, while 91% can pass through hepatic metabolism. Hence, compared to the liver, the intestinal wall is the main site where TU is significantly metabolised during first-pass effect.

An in Vitro Digestion Test That Reflects Rat Intestinal Conditions To Probe the Importance of Formulation Digestion vs First Pass Metabolism in Danazol Bioavailability from Lipid Based Formulations

2014 ◽  
Vol 11 (11) ◽  
pp. 4069-4083 ◽  
Author(s):  
Mette U. Anby ◽  
Tri-Hung Nguyen ◽  
Yan Yan Yeap ◽  
Orlagh M. Feeney ◽  
Hywel D. Williams ◽  
...  
Keyword(s):  
In Vitro Digestion ◽  
First Pass Metabolism ◽  
First Pass ◽  
Pass Metabolism

scholarly journals Gastroretentive drug delivery system of a lipid lowering agent

2013 ◽  
Vol 2 (9) ◽  
pp. 152-155
Author(s):  
D. Krishnarajan ◽  
N. Senthil Kumar ◽  
Rajesh Yadav
Keyword(s):  
Guar Gum ◽  
Lipid Lowering ◽  
In Vitro Dissolution ◽  
Wet Granulation ◽  
Natural Polymers ◽  
First Pass Metabolism ◽  
First Pass ◽  
Mucoadhesive Tablets ◽  
Pass Metabolism

The objective of this study was to develop mucoadhesive tablets of Simvastatin using natural polymers. Simvastatin has short biological half-life and high first pass metabolism hence which was designed to increase the gastric residence time which prolong the drug release. The tablets were prepared by wet granulation technique using Carbopol-934, guar gum, xanthine gum and chitosin as polymers. Formulations were evaluated for different parameters like hardness, friability, uniformity of weight, swelling characteristics, in vitro dissolution and kinetic studies. The dissolution was carried out for 12 hours in which the formulation with guar gum has shown highest dissolution release profile (F9). Thus the present study concludes that mucoadhesive tablets of simvastatin can be a good way to pass the extensive hepatic first pass metabolism and to improve the bioavailability of simvastatin.DOI: http://dx.doi.org/10.3329/icpj.v2i9.16077 International Current Pharmaceutical Journal, August 2013, 2(9): 152-155

scholarly journals Formulation and Evaluation of Orodispersible Tablet of Atorvastatin Calcium by Using Hibiscus rosa sinesis Mucilage as Natural Superdisintegrant

2019 ◽  
Vol 9 (6) ◽  
pp. 90-94
Author(s):  
Ashish Gupta ◽  
Juhi Bhadoria ◽  
G.N. Darwhekar
Keyword(s):  
Lipid Lowering ◽  
Content Uniformity ◽  
Atorvastatin Calcium ◽  
Drug Content ◽  
Orodispersible Tablets ◽  
Orodispersible Tablet ◽  
First Pass Metabolism ◽  
First Pass ◽  
Pass Metabolism

Orodispersible tablets (ODTs), also known as fast melt, quick melts, fast disintegrating have the unique property of disintegrating in the mouth in seconds without chewing and the need of water. Oral bioavailability of Atorvastatin Calcium is low (14%) and shows extensive intestinal clearance and first-pass metabolism, which is the main cause for the low systemic availability. In the present work, orodispersible tablets of Atorvastatin calcium were prepared by direct compression method using Hibiscus rosa sinesis mucilage as natural superdisintegrant with a view to enhance patient compliance and to avoid hepatic first pass metabolism and to improve its bioavailability. The prepared batches of tablets were evaluated for hardness, friability, drug content uniformity, wetting time, water-absorption ratio and in-vitro dispersion time. Short-term stability studies on the promising formulation indicated that there are no significant changes in drug content and in vitro dispersion time. Keywords: Orodispersible tablet, Atorvastatin Calcium, lipid-lowering agent, Superdisintegrant, Hibiscus Rosa Sinensis, Bioavailability, solubility. 

scholarly journals Formulation and Characterization of Isradipine as Oral Nanoemulsion

2020 ◽  
Vol 29 (1) ◽  
pp. 143-153
Author(s):  
Noor A. Sadoon ◽  
Mowafaq M. Ghareeb
Keyword(s):  
Oral Administration ◽  
Phase Diagrams ◽  
Polydispersity Index ◽  
Light Transmittance ◽  
Drug Content ◽  
First Pass Metabolism ◽  
First Pass ◽  
Nano Emulsion ◽  
Pass Metabolism

        Isradipine related to dihydropyridine (DHP) class of calcium channel blockers (CCBs). It is  used to treat hypertension, angina pectoris, as well as Parkinson disease. It goes under the BCS class II drug (low solubility-high permeability). The drug will experience extensive first-pass metabolism in liver, thus, oral bio-availability will be approximately15 to 24 %.         The aim of the study is preparing stable oral oil in water (o/w) nanoemulsion of isradipine to promote the colloidial dispersion of isradipine in the nano range, so that it may be absorded by intestinal lymphatic transport in order to avoid hepatic first-pass metabolism (israpidine undergoes 15-24% first pass metabolism) and increase drug bioavailability.        The solubility study was carried out in various vehicles for selecting best solvent  for dissolving isradipine. Pseudo-ternary phase diagrams is formed at (1:1, 1:2, 1:3, 1:4 and 2:1) ratios related to Smix (co-surfactant and surfactant).  There are 11 nano-emulsion was  prepared through the use of many concentrations of ( Transcutol, Tween20, and Triacetin). All formulations assessed for (in-vitro drug dissolution, pH measurement, viscosity, drug content, polydispersity index, particle size distribution, thermodynamic stability, dye test, and light transmittance). It is indicated that the extent as well as the rate of release regarding all the prepared formulations have considerably higher in comparison to that of crude drug powder. Results of characterization were explained that isradipine  nano emulsion (NE9) with S mix(1:4) : oil : deionized water (40: 5: 55) ratio was the optimized formula that has droplet size range (177.1nm), the lowest value of polydispersity index (0.12), the highest percent of drug content (99.7%) typical pH value for oral administration (5.21) , good percent of light transmittance (99.86 %), the range of viscosity (65.12 -25.2 m Pas. sec.) was suitable for oral administration, also the isradipine’s in vitro release has been considerably higher. It can be concluded that nano emulsion drug delivery system (DDS) can be considered as an encouraging method for improving the stability, dissolution and solubility of formulation. Keywords: Nanoemulsion, Isradipine  , Peudoternary phase diagrams.

scholarly journals FORMULATION, IN VITRO AND EX VIVO CHARACTERIZATION OF MUCOADHESIVE BUCCAL TABLETS FOR ANTIHYPERTENSIVE DRUG

2018 ◽  
Vol 11 (8) ◽  
pp. 402 ◽  
Author(s):  
Himabindu Peddapalli ◽  
Vasudha Bakshi ◽  
Narender Boggula
Keyword(s):  
Drug Release ◽  
Ex Vivo ◽  
Surface Ph ◽  
Ex Vivo Permeation ◽  
First Pass Metabolism ◽  
First Pass ◽  
Permeation Studies ◽  
Buccal Tablets ◽  
Pass Metabolism

Objective: Olmesartan belongs to a class of angiotensin II receptor blockers. It is used in the treatment of hypertension. However, it undergoes extensive hepatic first-pass metabolism, resulting in low oral bioavailability is about 26%. The aim of this study was to prepare and evaluate the mucoadhesive buccal tablets of olmesartan with a goal to increase the bioavailability and improve the patient compliance.Methods: Mucoadhesive buccal tablets were prepared by a direct compression technique using mucoadhesive polymers such as hydroxypropyl methylcellulose (HPMC K4M), sodium carboxymethylcellulose (SCMC), and Carbopol 934P. The tablets were evaluated for weight variation, thickness, hardness, friability, surface pH, swelling index, drug content uniformity, in vitro drug release, ex vivo mucoadhesive strength, ex vivo mucoadhesive time, and ex vivo permeation studies. The release kinetics was calculated to determine the drug release mechanism. Results: The physicochemical properties of all the formulations were shown to be within the limits. The optimized buccal tablets F2, F7, and F11 showed satisfactory drug release rates with the diffusion controlled mechanism. Optimized buccal tablets developed for olmesartan possess reasonable mucoadhesive strength, mucoadhesive time, and surface pH was in an acceptable salivary pH 6.76±0.28–6.89±0.34. The ex vivo permeation studies for optimized tablets were shown satisfactory drug permeation and could meet the target flux 0.991 mg h−1cm−2.Conclusion: The obtained results could be used as a platform to develop the buccal delivery of this drug, which bypasses the first-pass metabolism and results in the improvement of bioavailability. Hence, the present study concludes that the olmesartan could be delivered through the buccal route.

The pharmacologic selectivity of serotonin reuptake inhibitors

1993 ◽  
Vol 8 (S1) ◽  
pp. 5s-8s ◽  
Author(s):  
IF Tulloch
Keyword(s):  
Serotonin Reuptake ◽  
Tricyclic Antidepressants ◽  
Selective Inhibitor ◽  
Neurotransmitter Receptors ◽  
Marked Contrast ◽  
First Pass Metabolism ◽  
First Pass ◽  
Pass Metabolism

SummaryParoxetine is a highly potent and selective inhibitor of serotonin reuptake, with in vitro potency greater than that of fluoxetine, fluvoxamine, and sertraline. It has little affinity for a wide variety of neurotransmitter receptors, including catecholaminergic or histaminergic systems, in marked contrast to the tricyclic antidepressants. Paroxetine undergoes first-pass metabolism that is partially saturable to give metabolites that are pharmacologically inactive in vivo, unlike those of fluoxetine or sertraline.

Effect of various Polymers on Drug Release from Mucoadhesive Tablets of Cefixime Trihydrate

2021 ◽  
pp. 167-173
Author(s):  
Kumara Swamy Samanthula ◽  
Agaiah Goud Bairi ◽  
Shobha Rani Satla ◽  
Mahendra Kumar CB
Keyword(s):  
Drug Release ◽  
Diffusion Mechanism ◽  
In Vitro Release ◽  
In Vitro Dissolution ◽  
Content Uniformity ◽  
First Pass Metabolism ◽  
First Pass ◽  
Mucoadhesive Tablets ◽  
Pass Metabolism

Cefixime trihydrate (CT) is a third-generation cephalosporin antibiotic and is used in the management of various infections caused by Gram +ve as well as Gram – ve bacteria. It has a plasma half-life of 3-4 h. It has poor oral bioavailability due to hepatic first pass metabolism. Hence, an attempt was made to develop CT mucoadhesive tablets for buccal delivery to avoid first-pass metabolism and improved oral delivery. CT mucoadhesive tablets developed using HPMC K4M, Na-CMC, guar gum and chitosan as rate controlling polymers and mucoadhesive agent, respectively and compressed by direct compression method. The prepared CT mucoadhesive tablets were evaluated for hardness, weight variation, thickness, friability, drug content uniformity, assay, mucoadhesive strength and in vitro release. From the results, all the evaluated parameters were within the pharmacopoeial limits. The in-vitro dissolution studies indicated that the CTmucoadhesive tablets formulation (F2) showed 99.7±1.4 % of drug release after 8 h and chose as the optimized formulation. The kinetic models suggest that the drug release follows Higuchi’s kinetics and tablets drug release was controlled by a diffusion mechanism.

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