pass metabolism
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Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3301
Author(s):  
Bo-Eun Lee ◽  
Do-Kyung Kim ◽  
Hyunil Lee ◽  
Siyeong Yoon ◽  
Sin-Hyung Park ◽  
...  

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.


Author(s):  
Priyanka Joshi ◽  
Naveen Sharma ◽  
Megha Jain ◽  
Harsha Matoli ◽  
Vinay Jain

Aging have an impact on the pharmacokinetic and pharmacodynamic characteristics of drugs, resulting in clinically relevant safety and efficacy consequences. There appear to be a rise in gastrointestinal (GI) problems with age, and certain slight variations in the GI tract have been noted. Nevertheless, insufficient studies have been done on the impact of aging on the expression and activity of these GI transporters. Aging is associated with some reduction in first-pass metabolism that might be due to a decrease in liver mass and perfusion. Some medications with considerable first-pass metabolism, can have markedly enhanced bioavailability and, as a consequence bioavailability. Other high clearance (CL) medications have identical bioavailability in both young and old individuals. However, at the other hand, the first-pass activation of some prodrugs, may be slowed or decreased, leading to a reduction in bioavailability. Some drugs may have a low bioavailability when taken orally, benefitted from transdermal administration. There are still no specific age-related liver ailments, routine clinical tests of liver function do not vary substantially with age, the course, and outcome of some liver diseases can be affected by age. The characteristic of high or low extraction of a drug by the liver has been attributed to whether the metabolic clearance (CL) of a drug falls or remains unchanged with age. Reduction in renal function in elderly subjects, particularly glomerular filtration rate, affects the clearance of many drugs such as water-soluble antibiotics and nonsteroidal anti-inflammatory drugs. The therapeutic significance of these declines in renal excretion is governed by the drug's expected toxicity. Many drugs show their effects specially in old age patients in different manner and depend on age related factors. It must take appropriate precautions for administering of different drugs to the old age patients.


Author(s):  
JISHA MOHANAN ◽  
SEENIVASAN PALANICHAMY ◽  
ARUL KUTTALINGAM ◽  
DAMODHARAN NARAYANASAMY

Objective: The study aimed to prepare and characterize inclusion complexes of tacrolimus with β-cyclodextrin to improve its solubility and to formulate them into sublingual fast disintegrating tablets with a view to bypass the first-pass metabolism. Methods: Tacrolimus: β-cyclodextrin inclusion complexes (1:1 and 1:2 molar proportions) were prepared using the kneading method. Their characterization was accomplished by determining the drug content, solubility, Attenuated Total Reflection-Infrared Spectroscopy (ATR-IR), Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), and powder X-Ray Diffraction analysis (pXRD). These were then formulated to fast disintegrating tablets and evaluated for precompression as well as post compressional characteristics. Results: SEM analysis showed the inclusion complexes as rough, non-porous, irregular surfaced aggregate particles. DSC and pXRD analyses confirm the crystallinity change and partial conversion to the amorphous form of the drug in the inclusion complexes. From the solubility studies, it was observed that both the inclusion complexes of 1:2 molar ratio (14.82±0.889 µg/ml) and 1:1 molar ratio (12.72±0.1004 µg/ml) improved the aqueous solubility to greater extents in comparison to that of the pure drug (3.05±0.121 µg/ml). All the tablet formulations showed good precompression and mechanical properties. The inclusion complex loaded tablets exhibited a superior drug release pattern when compared to tablets prepared with tacrolimus alone. The optimized formulation (TT3) showed an in vitro disintegration time of 34.33 s and a percent drug release of 97.87. Conclusion: The inclusion complex formulation combined with the sublingual route of administration can be expected to result in an improved bioavailability of tacrolimus by increasing its solubility and bypassing first-pass metabolism.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1707
Author(s):  
Zoe Coombes ◽  
Katie Plant ◽  
Cristina Freire ◽  
Abdul W. Basit ◽  
Philip Butler ◽  
...  

Following oral administration, the bioavailability of progesterone is low and highly variable. As a result, no clinically relevant, natural progesterone oral formulation is available. After oral delivery, first-pass metabolism initially occurs in the intestines; however, very little information on progesterone metabolism in this organ currently exists. The aim of this study is to investigate the contributions of liver and intestine to progesterone clearance. In the presence of NADPH, a rapid clearance of progesterone was observed in human and rat liver samples (t1/2 2.7 and 2.72 min, respectively). The rate of progesterone depletion in intestine was statistically similar between rat and human (t1/2 197.6 min in rat and 157.2 min in human). However, in the absence of NADPH, progesterone was depleted at a significantly lower rate in rat intestine compared to human. The roles of aldo keto reductases (AKR), xanthine oxidase (XAO) and aldehyde oxidase (AOX) in progesterone metabolism were also investigated. The rate of progesterone depletion was found to be significantly reduced by AKR1C, 1D1 and 1B1 in human liver and by AKR1B1 in human intestine. The inhibition of AOX also caused a significant reduction in progesterone degradation in human liver, whereas no change was observed in the presence of an XAO inhibitor. Understanding the kinetics of intestinal as well as liver metabolism is important for the future development of progesterone oral formulations. This novel information can inform decisions on the development of targeted formulations and help predict dosage regimens.


2021 ◽  
Vol 43 (3) ◽  
pp. 1592-1605
Author(s):  
Christina E. Larder ◽  
Michèle M. Iskandar ◽  
Stan Kubow

Collagen hydrolysates (CHs) are composed of bioactive peptides (BAPs), which possess health enhancing properties. There is a knowledge gap regarding the bioavailability of these BAPs that involves intestinal transport and hepatic first pass effects. A simulated gastrointestinal model was used to generate digesta from two CHs (CH-GL and CH-OPT), which were applied to a novel transwell co-culture of human intestinal epithelium cell line-6 (HIEC-6) and hepatic (HepG2) cells to simulate in vivo conditions of absorption and first pass metabolism. Peptide transport, hepatic first pass effects, and bioavailability were determined by measuring BAPs (Gly-Pro, Hyp-Gly, Ala-Hyp, Pro-Hyp, Gly-Pro-Hyp) using an innovative capillary electrophoresis method. All peptides were transported across the intestinal cell layer to varying degrees with both CHs; however, Gly-Pro-Hyp was transported only with CH-GL, but not CH-OPT. Notable hepatic production was observed for Ala-Hyp with both CH treatments, and for Pro-Hyp and Gly-Pro with CH-GL only. All peptides were bioavailable (>10%), except for Gly-Pro-Hyp after CH-OPT. Overall, a high degree of transport and hepatic first pass effects on CH-derived BAPs were observed. Further research is needed to explore the hepatic mechanisms related to the production of BAPs and the bifunctional effects of the bioavailable BAPs noted in this study.


2021 ◽  
Vol 12 (9) ◽  
pp. 1-5
Author(s):  
Biraj Jung Khadka ◽  
Madhushree H S ◽  
Ganesh Puttur

Basti Chikitsa is a prime treatment modality among the Panchakarma. It has not only curative aspects but also preventive and promotive aspects. Basti is the prime treatment for vata dosha but is also useful for the diseases caused by pitta dosha, kapha dosha as well as rakta and their combinations. Different permutations and combinations of basti dravyas give the wide option for the physician to treat all categories of diseases in all the age groups. Unlike Vamana and Virechana, Basti can be administered in all the age groups & can be administered in all the stages & variety of diseases. According to the pharmacokinetics it is also proven that rectal drugs administration might exceed the oral value due to partial avoidance of hepatic first pass metabolism. More than 500 million neurons are present in the ENS (Enteric Nervous System) and hence it is called “second brain”. Basti may act over the receptors of the ENS to stimulate the CNS causing secretion of required hormones or other chemicals. This article evaluates the validity and importance of Basti being termed as Ardha chikitsa or Sampoorna chikitsa.


2021 ◽  
Vol 16 (3) ◽  
pp. 235-240
Author(s):  
Kapil Kumar ◽  
Gurleen Kaur ◽  
Seema ◽  
Deepak Teotia ◽  
Ikram

Buccal patches are the types of formulations in which the drug is administered through buccal mucosa. these patches are or placed in between the gums and the for the pharmacological response. The main advantage of these patches is there is no first pass metabolism takes place and easily absorb in systemic circulation through themucosa .the main objective of this drug delivery system is to elevate or increase the bioavailability of the drug. the review informs about the steps involve in the preparation of buccal patch and to promote the awareness towards this type of drug delivery system. This article intends to analyze the overall profile of Buccal Patches and scope of future advances.


Author(s):  
Bhaskar Mohite ◽  
Rakesh Patel ◽  
Nandu Kayande

Acyclovir is an anti-viral, which has been used in the treatment of vaginal disorder. Acyclovir is almost completely absorbed after oral administration but has low bioavailability of about 10-15% because of first pass metabolism. As first pass metabolism removes approximately 85-90% of the drug, so for clinical efficacy of the drug it should be frequently administered. Hence an attempt has been made to produce sustained release dosage form of the acyclovir which can be specifically employed for the treatment of vaginal disordered by Herpes simplex virus. The Mucoadhesive tablets of acyclovir has been prepared by direct compression methods and evaluated for various parameter such as thickness, friability, hardness, drug content, weight variation, swelling index, surface pH, bioadhesive force, bioadhesive time, drug release etc. The kinetic data was applied to the optimized formulations. So formulation of acyclovir in a vaginal mucoadhesive tablet dosage form will decrease the frequency of administration, which can lead to an improvement in patient adherence and thereby improving its clinical efficacy.


2021 ◽  
Vol p5 (6) ◽  
pp. 3135-3142
Author(s):  
Tanuja Mehta ◽  
Uttam Kumar Sharma ◽  
Bhawana Mittal ◽  
Shikha Pandey

Background- Panchkarma is a group of procedures known for its preventive, promotive, prophylactic and rejuve- nating properties as well as radicle cure. Nasya is one of the Panchkarma treatments. Among the various forms of Nasya, Dhumnasya is a very effective type of Nasya which has further been classified into different types based on various potency of herbs with their respective properties. Aim and Objective: To find out the role of Dhumnasya in the preventive and curative aspects. Material and Methods: Classics of Ayurveda having references regarding Nasya, Modern literature, published articles in peer-reviewed journals, published books and subject-related material available online have been screened, compiled, organized and described systematically. Result: In Dhumnasya medicinal herbs with other constituents are burnt in such an effective manner to produce a medicated fume contain- ing volatile phytochemical of herbs, which when inhaled through nasal route exerts their efficient role in both pre- vention and treatment of various forms of disease both at a local and systemic level. Conclusion: In this review article, it has been tried to focus on the preventive and curative aspect of Dhumnasya so to help to address issues related to poor bioavailability, slow absorption, drug degradation and adverse event in the GIT tract and avoid the first-pass metabolism in the liver and discover the advantage of smoke based therapies as rapid delivery to the brain, more efficient pulmonary absorption and become the suitable substitute for the oral and parental administration. Keywords: Panchkarma, Dhumnasya, Nasya, Medicated smoke.


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