First-pass Metabolism In Liver Research Articles

Dietary dicarboxylic acids provide a non-storable alternative fat source that protects mice against obesity.

Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an alternative source of dietary fat have not been explored. Here, we fed dodecanedioic acid, a 12-carbon dicarboxylic (DC12), to mice at 20% of daily caloric intake for nine weeks. DC12 increased metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. We observed DC12-specific breakdown products in liver, kidney, muscle, heart, and brain, indicating that oral DC12 escaped first-pass liver metabolism and was utilized by many tissues. In tissues expressing the "a" isoform of acyl-CoA oxidase-1 (ACOX1), a key peroxisomal fatty acid oxidation enzyme, DC12 was chain shortened to the TCA cycle intermediate succinyl-CoA. In tissues with low peroxisomal fatty acid oxidation capacity, DC12 was oxidized by mitochondria. In vitro, DC12 was catabolized even by adipose tissue and was not stored intracellularly. We conclude that DC12 and other dicarboxylic acids may be useful for combatting obesity and for treating metabolic disorders.

A Comprehensive Review on Role of Polymers in Transdermal Drug Delivery System

Transdermal drug delivery system has been emerged as one of the most effective controlled drug release system in topical formulation as it doesn’t undergo first pass metabolism in liver and can be directly absorbed into the systemic circulation. Polymers are used in TDDS as to increase its effectiveness in the control release of drug from the transdermal patch. Use of polymers in the TDDS has decreased the control release rate of drug from the patch. Use of polymers in combination has given more effectiveness of the drug release. This article gives a quality of information about the use of polymers in the Transdermal drug delivery system. Polymers also help in the adhesive nature of the drug to the skin and promote more extent of drug release from the dosage form. An advance in the use and amount of polymers used in the TDDS has been increased recently. This article provides the information about the use of Natural, semisynthetic and synthetic polymers in the TDDS. Use of natural polymers has been showed more impact in the TDDS and their use has showed fewer side effects like irritation, allergy, and this has been increased patient compliance and more effectiveness in drug release. Semisynthetic and synthetic polymers has been developed and used excessively in the TDDS for effective control release of the drug from the patches. A transdermal patch is defined as medicated adhesive patch which is placed above the skin to deliver a pre-determined dose of medication via skin with a predetermined rate of release to reach into the bloodstream. Article Details

Molecular Complex of HSIM-loaded Polymeric Nanoparticles: Potential Carriers in Osteoporosis.

Statins, especially simvastatin promote bone formation by stimulating the activity of osteoblasts and suppressing osteoclast activity via the BMP-Smad signaling pathway. Statins present the liver first-pass metabolism. This study attempts to fabricate and evaluate simvastatin functionalized hydroxyapatite encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles (HSIM-PLGA NPs) administered subcutaneously with sustained release properties for effective management of osteoporosis. Simvastatin functionalized hydroxyapatite (HSIM) was prepared by stirring and validated by docking studies, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffraction (XRD). Further, HSIM-loaded PLGA nanoparticles (HSIM-PLGA NPs) were developed via the solvent emulsification method. The nanoparticles were evaluated for zeta potential, particle size, entrapment efficiency, stability studies, and in vitro drug release studies. in vitro binding affinity of nanoparticles for hydroxyapatite was also measured. Bone morphology and its effect on bone mineral density were examined by using a glucocorticoid-induced osteoporosis rat model. The optimized nanoparticles were found to be amorphous and showed no drug-polymer interaction. The particle size of formulated nanoparticles varied from 196.8 ± 2.27nm to 524.8 ± 5.49 nm and the entrapment efficiency of nanoparticles varied from 41.9 ± 3.44% to 70.8 ± 4.46%, respectively. The nanoparticles showed sustained release behaviour (75% in 24 hr) of the drug followed by non-fickian drug release. The nanoparticles exhibited high binding affinity to bone cell receptors, increasing bone mineral density. A significant difference in calcium and phosphorous levels was observed in disease and treatment rats. Porous bone and significant improvement in porosity were observed in osteoporotic rats and treated rats, respectively (P < 0.05). Bone-targeting nanoparticles incorporating functionalized simvastatin can target bone. Thus, in order to distribute simvastatin subcutaneously for the treatment of osteoporosis, the developed nanoparticles may act as a promising approach.

Adaptogenic plants within food supplement

Adaptogenic plants have been recognized for their ability to enhance the body's capacity to adapt and withstand various stressors. This article explores the concept of adaptogens and their role in promoting resilience, tolerance, and adaptation to stress. Plant adaptogens are preferred over synthetic alternatives due to their safety, ability to normalize body functions, and the complex combination of compounds they contain. These natural extracts work synergistically to provide health benefits, unlike isolated compounds. Adaptogens act on multiple levels, modulating immunity, endocrine function, neurotransmitters, and signaling pathways. They help maintain homeostasis and can be used to prevent and manage health disorders resulting from imbalances in the body. The modern lifestyle's increasing prevalence of lifestyle disorders necessitates the consideration of adaptogenic food supplements. These supplements can prevent chronic diseases, improve quality of life, and counteract the declining ability of the body to combat stress. Taking adaptogens in the form of gummies offers distinct advantages, including convenience, compliance, and higher bioavailability. Gummies bypass the liver's first-pass metabolism, ensuring the efficient absorption of active ingredients. As adaptogens are often used long-term, gummies provide a suitable and enjoyable means of incorporating these beneficial plant extracts into daily routines. Choosing high-quality brands is essential for optimal results.

Modelling uptake and transport of therapeutic agents through the lymphatic system

The ability of the lymphatic network to absorb large molecules and bypass the first-pass liver metabolism makes it appealing as a delivery system for therapeutic substances. In most cases, the drug is injected into the subcutaneous tissue and must negotiate the tissue space, before being drained via the lymphatics. Tracking the transport of drug molecules through this route is challenging, and computational models of lymphatic drainage can play an important role in assessing the efficacy of a proposed delivery strategy. The three-dimensional computational model we present here of the peripheral lymphatic network and surrounding interstitium is informed by anatomical data, and quantifies the degree to which uptake and transit times are affected by drug particle size, physiological flow rates, and specifics of drug injection.

Formulation and Characterization of Isradipine Nanoparticle for Dissolution Enhancement

Isradipine belong to dihydropyridine (DHP) class of calcium channel blockers (CCBs). It is used in the treatment of hypertension, angina pectoris, in addition to Parkinson disease. It goes under the BCS class II drug (low solubility-high permeability). The drug will experience extensive first-pass metabolism in liver, therefore, oral bio-availability will be approximately15 to 24 %.&#x0D; &#x0D; The aim of this study was to formulate and optimize a stable nanoparticles of a highly hydrophobic drug, isradipine by anti-solvent microprecipitation Method to achieve the higher in vitro dissolution rate, so that it will be absorbed by intestinal lymphatic transport in order to avoid hepatic first-pass metabolism and improve drug bioavailability.&#x0D; &#x0D; Twenty one formulas of Isradipine nanoparticles were prepared by antisolvent precipitation method utilizing one of these polymers (Poloxamer 188, PVP-k30, HPMC E5, PVA, Poloxamer 407, and Soluplus) at different drugs: polymer ratios. The polymer type, the drug to polymer ratio, ultrasonication power and the effect of addition of co-stabilizer on the particle size, and polydispersity index (PDI) were investigated.&#x0D; &#x0D; Among all the prepared nanoparticles formulas, formula (F9) which contain Soluplus as a stabilizer at polymer: drug ratio of (1:0.75) and solvent: antisolvent ratio of (1:9) was considered as the optimum formula which shows good evaluation parameters in addition to the increment in the solubility to about 10 times than that of the pure drug. The investigations of the drug–excipients compatibility studies by FTIR and DSC, crystalline state by P-XRD, surface morphology by SEM were done. Moreover, the analysis by DSC and SEM of the nanoparticles of the selected formula (F12) indicate a reduction in the crystallinity and amorphization of the drug. It can be concluded that the dissolution rate of Isradipine was significantly increased through particle size reduction to nanosize.&#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D;

Innovative Mucoadhesive Precursor of Liquid Crystalline System Loading Anti-Gellatinolytic Peptide for Topical Treatment of Oral Cancer.

Current researches report an actual benefit of a treatment for oral cancer via inhibition of proteolytic matrix metallopro-teinases (MPP) with a peptide drug, called CTT1. However, peptides present poor oral bioavailability. Topical administration on oral mucosa avoids its passage through the gastrointestinal tract and the first-pass liver metabolism, but the barrier function of the oral mucosa can impair the permeation and retention of CTT1. The objective of this study is to incorporate CTT1 into a mucoadhesive precursor of liquid crystalline system (PLCS) as an interesting strategy for the topical treatment of oral cancer. PLCS consisting of oleic acid, ethoxylated 20 and propoxylated cetyl alcohol 5, polyethyleneimine (P)-associated chitosan (C) dispersion and CTT1 (FPC-CTT1) was developed and characterized by polarized light microscopy (PLM) and small-angle X-ray scattering (SAXS). In vitro permeation and retention across esophageal mucosa, In vitro cytotoxicity towards tongue squamous cell carcinoma cells, and in vivo evaluation of vascular changes using the chick embryo chorioallantoic membrane (CAM) model were performed. PLM and SAXS showed that FPC-CTT1acted as PLCS, because it formed a lamellar liquid crystalline system after the addition of artificial saliva. FPC-CTT1increased approximately 2-fold the flux of permeation and 3-fold the retention of CTT1 on the porcine esophageal mucosa. CTT1 does not affect cell viability. CAM tests showed that FPC preserved the blood vessels and it can be a safe formulation. These findings encourage the use of the FPC-CTT1 for topical treatment of oral cancer.

Transdermal Diclofenac Patch versus Intra Muscular Diclofenac Injection for the Management of Pain in the Post Operative Patients in a Teritiary Teaching Institute

Background: Pain management in immediate postoperative period is an extremely important but herculean task. As oral medication is not possible at this stage, it is injectable analgesia which is put to task. In countries like India, where efficacy and cost both count, intramuscular diclofenac is the most commonly employed analgesic. Methodology: The study was cross sectional by using questionnaire in 80 healthy adult subjects of either sex undergoing Hernia correction surgery under spinal anaesthesia. The subjects were assigned into two groups (Group I and Group P) by computer generated randomization table to receive intramuscular diclofenac 75mg or transdermal diclofenac patch 100mg immediately after spinal anaesthesia. The patients were monitored for pain using Visual Analogue Scale. Duration of analgesia and request for rescue analgesic (Tramadol 2mg/kg) were noted in both the groups. The study ended when patients had a VAS &gt; 8 or at first request for analgesic. Result and Conclusion: It was concluded that if applied with proper planning, diclofenac patch was as effective as diclofenac injection but at the same time administration of patch is devoid of pain, local side effects, drug destruction by stomach and digestive enzymes and first pass metabolism in liver.

The Interplay Between Liver First-Pass Effect and Lymphatic Absorption of Cannabidiol and Its Implications for Cannabidiol Oral Formulations.

For highly lipophilic drugs, passage into the intestinal lymphatic system rather than the portal vein following oral administration may represent a major alternative route of delivery into the general circulation. Increasing intestinal lymphatic transport provides an effective strategy to improve oral bioavailability when hepatic first-pass metabolism is a major rate-limiting step hampering access to the systemic circulation after oral dosing. The transfer of orally administered, highly lipid-soluble drugs to the lymphatic system is mediated by their association with chylomicrons, large intestinal lipoproteins that are assembled in the enterocytes in the presence of long-chain triglycerides or long-chain fatty acids. Due to its very high lipophilicity, cannabidiol (CBD) has physicochemical features (e.g. logP = 6.3) consistent with an oral absorption mediated at least in part by transport via the intestinal lymphatic system. CBD also undergoes extensive first-pass hepatic metabolism. Formulation changes favoring diversion of orally absorbed CBD from the portal to the lymphatic circulation pathway can result in reduced first-pass liver metabolism, enhanced oral bioavailability, and reduced intra- and intersubject variability in systemic exposure. In this manuscript, we discuss (1) evidence for CBD undergoing hepatic first-pass liver metabolism and lymphatic absorption to a clinically important extent; (2) the potential interplay between improved oral absorption, diversion of orally absorbed drug to the lymphatic system, and magnitude of presystemic elimination in the liver; and (3) strategies by which innovative chemical and/or pharmaceutical delivery systems of CBD with improved bioavailability could be developed.

Formulation and Characterization of Isradipine as Oral Nanoemulsion

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 %. &#x0D; 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.&#x0D; 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).&#x0D; 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.&#x0D; Keywords: Nanoemulsion, Isradipine , Peudoternary phase diagrams.

Hydroxychloroquine as an aerosol might markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 infection

Covid-19 is a new coronavirus disease first described in December 2019. This respiratory illness is severe and potentially fatal. Severe cases make up to 15%, lethality ranges between 1.5 and more than 10%. What is urgently needed is an efficient pharmacological treatment for the treatment of severe cases. During the infection of alveolar epithelial cells of the lung, the ACE2 receptor has a central function. The antimalarial drugs chloroquine phosphate (CQ) and hydroxychloroquine (HCQ) impair in vitro the terminal glycosylation of ACE2 without significant change of cell-surface ACE2 and, therefore, might be potent inhibitors of SARS-CoV-2 infections. Starting inhibition at 0.1 µM, CQ completely prevented in vitro infections at 10 µM, suggesting a prophylactic effect and preventing the virus spread 5 h after infection. In a first clinical trial, CQ was effective in inhibiting exacerbation of pneumonia, improving lung imaging findings, promotion of virus-negative conversion, and shortening the disease. In addition, HCQ, which is three times more potent than CQ in SARS-CoV-2 infected cells (EC50 0.72 µM), was significantly associated with viral load reduction/disappearance in COVID-19 patients compared to controls. Theoretically, CQ and HCQ could thus be effectively used in the treatment of SARS-CoV pneumonia. From a pharmacological standpoint, however, the major problems of oral treatment with these drugs are possible severe side effects and toxicity. Concretely, this relates to (a) the inconsistent individual bioavailability of these drugs at the alveolar target cells, depending on intestinal resorption, hepatic first-pass metabolism and accumulation in liver, spleen and lung, and (b) the need for a relatively high concentration of 1–5 µM at the alveolar surface.Therefore, we propose in a first dose estimation the use of HCQ as an aerosol in a dosage of 2–4 mg per inhalation in order to reach sufficient therapeutic levels at the alveolar epithelial cells. By using a low-dose non-systemic aerosol, adverse drug reactions will markedly be reduced compared with oral application. This increase in tolerability enables a broader use for prevention and after contact with an infected person, which would be an advantage especially for the high-risk, often multi-morbid and elderly patients.Empirical data on self-medication with a one-week aerosol application by two of the authors is presented. Inhalation was well tolerated without relevant side effects.

Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules

Hypertension is a diverse illness interlinked with cerebral, cardiovascular (CVS) and renal abnormalities. Presently, the malady is being treated by focusing on Renin- angiotensin system (RAS), voltage-gated calcium channels, peripheral vasodilators, renal and sympathetic nervous systems. Cardiovascular and renal abnormalities are associated with the overactivation of RAS, which can be constrained by angiotensin- converting enzyme inhibitors (ACEIs), angiotensin II (Ang-II) -AT1 receptor blockers (ARBs) and renin inhibitors. The latter is a new player in the old system. The renin catalyzes the conversion of angiotensinogen to Angiotensin I (Ang-I). This can be overcome by inhibiting renin, a preliminary step, eventually hinders the occurrence of the cascade of events in the RAS. Various peptidomimetics, the first-generation renin inhibitors developed six decades ago have limited drug-like properties as they suffered from poor intestinal absorption, high liver first-pass metabolism and low oral bioavailability. The development of chemically diverse molecules from peptides to nonpeptides expanded the horizon to achieving direct renin inhibition. Aliskiren, a blockbuster drug that emerged as a clinical candidate and got approved by the US FDA in 2007 was developed by molecular modeling studies. Aliskiren indicated superior to average efficacy and with minor adverse effects relative to other RAS inhibitors. However, its therapeutic use is limited by poor oral bioavailability of less than 2% that is similar to first-generation peptidic compounds. In this review, we present the development of direct renin inhibitors (DRIs) from peptidic to nonpeptidics that lead to the birth of aliskiren, its place in the treatment of cardiovascular diseases and its limitations.

Fabrication, optimization, and in vitro/in vivo evaluation of diclofenac epolamine flash tablet.

The objective of this work was to design a diclofenac epolamine (DE) flash tablets (FTs) intended to dissolve in the mouth saliva, thereby improving the DE bioavailability and reducing its first-pass liver metabolism. Design-Expert software was used to build a 31.22 full factorial design (12 runs). FTs were fabricated using lyophilization process. The dissolution response was selected to pick the optimized run. The results indicate that the optimized run (R1) showed the fastest drug dissolution (total dissolution in 12min). The predicted run (Rp) showed a desirability of about 0.93. Differential scanning calorimetry(DSC) analysis results showed a decrease in the drug melting point of the R1 formulation. Fourier-transform infrared spectroscopy (FTIR) showed the compatibility of the drug with other components of formulation, X-ray powder diffraction (XRPD) analysis showed the evolution of the drug physical state from a crystalline to an amorphous formand scanning electron microscopy(SEM) divugled the disappearance of drug crystals in gelatin strands. The results of the pharmacokinetic study performed in 6 human volunteers evidenced an increase in the maximum DE concentration in plasma and, consequently, an increased bioavailability of the FT formulation as compared with a reference formulation(Fr). Concisely, the developed FTs (R1) showed promising results which could be able to enhance oral bioavailability, reduce the therapeutic dose of the drug, and abate of the complications accompanied with conventional dosage forms. Graphical abstract.

Metabolism of the lipophilic phycotoxin 13-Desmethylspirolide C using human and rat in vitro liver models

13-Desmethylspirolide C (13-SPX-C) is a phycotoxin produced by dinoflagellates which can accumulate in shellfish. 13-SPX-C induces neurotoxic effects in rodents through blockade of nicotinic acetylcholine receptors. As no human intoxication has been to date attributed to the consumption of 13-SPX-C-contaminated seafood, this toxin is not regulated according to the Codex Alimentarius. Nevertheless, shellfish consumers can be exposed to 13-SPX-C via shellfish consumption. In order to follow the fate of the toxin after ingestion and to verify whether metabolic detoxification could explain the lack of human intoxications, we assessed the metabolism of 13-SPX-C using several in vitro liver systems. First, both phase I and II reactions occurring with rat and human liver S9 fractions were screened. Our results indicated that 13-SPX-C was almost completely metabolized with both rat and human liver S9. Using a receptor binding assay towards nicotinic acetylcholine receptors we demonstrated that the resulting metabolites showed less affinity towards nicotinic acetylcholine receptors than 13-SPX-C. Finally, we showed that 13-SPX-C induced a pronounced increase of gene expression of the drug-metabolizing enzyme cytochrome P450 (CYP) CYP1A2. The role of this CYP in 13-SPX-C metabolism was clarified using an innovative in vitro tool, CYP1A2-Silensomes™. In summary, this study highlights that liver first-pass metabolism can contribute to the detoxification of 13-SPX-C.

Fe-MIL-100 as drug delivery system for asthma and chronic obstructive pulmonary disease treatment and diagnosis

Abstract The Metal-Organic Framework material Fe-MIL-100 was tested for use as a biocompatible, non-toxic carrier for theophylline, a methylxanthine-based drug, that is used commercially for asthma and chronic obstructive pulmonary disease. The composite of Fe-MIL-100 and the drug, which is intended for inhalatory treatment and possible theranostic to avoid the first-pass metabolism in liver, was characterized to confirm the drug loading (32%, standard deviation: ± 1.2) and its prolonged release (46%, standard deviation: ± 1.54). This proved potential for therapeutic use. Biotoxicty tests (PrestoBlue and ToxiLight) showed minimal influence of high concentrations of Fe-MIL-100 on the viability of cells (human epithelial cells A549, and murine macrophages, RAW 246.9). The measurement of stress induced in the living cells by Fe-MIL-100 was also estimated by a measurement of the level of oxygen reactive species generation. All these results confirmed that Fe-MIL-100 can be used safely as carrier for potential application in inhalable treatments.

Lymphatic Drug Absorption via the Enterocytes: Pharmacokinetic Simulation, Modeling, and Considerations for Optimal Drug Development.

Most orally administered drugs gain access to the systemic circulation by direct passage from the enterocyte layer of the intestinal tract to the mesenteric blood capillaries. Intestinal lymphatic absorption is another pathway that certain drugs may follow to gain access to the systemic circulation after oral administration. Once absorbed, drug diffuses into the intestinal enterocyte and while in transit may associate with fats as they are processed into chylomicrons within the cells. The chylomicron-associated drug is then secreted from the enterocyte into the lymphatic circulation, thus avoiding the hepatic first-pass liver metabolism, and ultimately entering to the systemic circulation for disposition and action. Due to the possibility of parallel and potentially alternative absorptive pathways, mesenteric blood capillary and lymphatic drug exposure are both potential pathways of systemic availability for any individual drug. In this report, an in silico modeling approach was adopted to delineate the salient pharmacokinetic features of lymphatic absorption, and provide further guidance for the rationale design of drugs and drug delivery systems for lymphatic drug transport. The importance of hepatic extraction ratio, absorption lag time, lipoprotein binding, and the influence of competing portal and lymphatic pathways for systemic drug availability were explored using simulations. The degree of hepatic extraction was found to be an essential consideration when examining the influence of lymphatic uptake to overall oral drug bioavailability. Lymphatic absorption could potentially contribute to multiple peaking phenomena and flip flop pharmacokinetics of orally administered drugs.

Metabolic profiling of corylin in vivo and in vitro

Corylin, an phenolic compound from Psoralea corylifolia, has been reported with various pharmacological properties but has poor bioavailability due to massive metabolism. In this study, twelve metabolites of corylin mainly involving in oxidation, hydration, glucuronidation and sulfation were detected in mice. Furthermore, the oxidation and hydration of corylin (M4) in human liver microsomes (HLM) and human intestine microsomes (HIM) were both efficient with high CLint (intrinsic clearance) values of 24.29 and 42.85 μL/min/mg, respectively. CYP1A1, 1B1 and 2C19 contributed most for M4 with the CLint values of 26.63, 33.09 and 132.41 μL/min/mg, respectively. Besides, M4 was strongly correlated with phenacetin-N-deacetylation (r = 0.885, p = 0.0001) and tolbutamide-4-oxidation (r = 0.727, p = 0.001) in twelve individual HLMs, respectively. In addition, corylin was efficiently glucuronidated (M7) in HLM (125.33 μL/min/mg) and in HIM (108.74 μL/min/mg). UGT1A1 contributed the most for M7 with the CLint value of 122.32 μL/min/mg. Meanwhile, M7 was significantly correlated with β-estradiol-3-O-glucuronidation (r = 0.742, p = 0.006) in twelve individual HLMs. Moreover, the metabolism of corylin showed marked species differences. Taken together, corylin was subjected to massive first-pass metabolism in liver and intestine, while CYP1A1, 1B1, 2C19 and UGT1A1 were the main contributors. Finally, the proposed metabolic pathway of corylin involed CYP and UGT isoforms were summarized, which could help to understand the metabolic fate of corylin in vivo.

Enhanced Oral Bioavailability of Diltiazem by the Influence of Gallic Acid and Ellagic Acid in Male Wistar Rats: Involvement of CYP3A and P-gp Inhibition.

The oral bioavailability of diltiazem is very low due to rapid first pass metabolism in liver and intestine. The purpose of the study was to investigate the effect of gallic acid and ellagic acid on intestinal transport and oral bioavailability of diltiazem in rats. The intestinal transport and permeability of diltiazem was evaluated by in vitro non-everted sac method and in situ single pass intestinal perfusion study. The oral pharmacokinetics was evaluated by conducting oral bioavailability study. The intestinal transport and apparent permeability of diltiazem were significantly enhanced in duodenum, jejunum, and ileum of gallic and ellagic acid-treated groups. The effective permeability of diltiazem was significantly enhanced in ileum part of gallic and ellagic acid-treated groups. When compared with control group, the presence of these two phytochemicals significantly enhanced the area under plasma concentration-time curve and the peak plasma concentration of diltiazem (Cmax ). Gallic acid and ellagic acid significantly increased the bioavailability of diltiazem due to the inhibition of both CYP3A-mediated metabolism and P-glycoprotein-mediated efflux in the intestine and/or liver. Based on these results, the clinical experiments are warranted for the confirmation to reduce the dose of diltiazem when concomitantly administered with these phytochemicals. Copyright © 2017 John Wiley & Sons, Ltd.

Development of Salbutamol Sulphate fast disintegrating sublingual tablets with enhanced bioavailability and improved clinical efficacy for potential treatment of asthma

Salbutamol Sulphate (SS) as a model bronchodilator drug undergoes first pass metabolism in liver, which has an oral bioavailability of only 50% of the administrated dose. Thus, the aim of this study was to attain rapid absorption and improved bioavailability, with subsequent immediate rapid onset of pharmacological effect. This work introduces a new design of SS fast disintegrating sublingual tablets (FDSTs) using a full factorial design (23) with three independent variables: the type of superdisintegrant (Ac-di-sol or Polyplasdone-XL), its concentration (3% or 5%w/w) and the binder type (Avicel PH101 or PEG6000). The formula T7 containing Polyplasdone-XL (5%w/w) with Avicel PH101 (10%w/w) had the least disintegration time (12.83 ± 0.7 s) and the highest dissolution rate (100 ± 2.6%), hence was selected for pharmacokinetic study in human volunteers. T7 showed Cmax of 19.36 ± 2.64 μg/ml, tmax of 1.33 ± 0.24 h; the mean AUC(0-8) was found to be 75.059 ± 7.55 μg h/ml and the AUC (0-∞) of 90.554 ± 8.027 μg h/ml. The relative bioavailability of T7 was 129.92% when compared to Ventolin® tablets. The clinical evaluation of T7 in fourteen asthmatic patients showed significant difference in forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and peak expiratory flow rate (PEFR) when compared to Ventolin® tablets using ZAN spirometry.

Diclofenac patch: a better alternative to injectable diclofenac in postoperative pain management

Background: Pain management in immediate postoperative period is an extremely important but herculean task. As oral medication is not possible at this stage, it is injectable analgesia which is put to task. In countries like India, where efficacy and cost both count, intramuscular diclofenac is the most commonly employed analgesic. It is painful and full of side effects. As ideal analgesic is still an illusion, so search for it comes out with some option which is better than the existing ones. Methods: In a similar effort we compared the analgesic effects of diclofenac transdermal patch (100mg)-Nupatch and diclofenac intramuscular injection (75 mg) in the management of post-operative pain in terms of efficacy, duration, quality of analgesia on visual analogue scale and adverse effects of both in short term use. Results: It was concluded that if applied with proper planning, diclofenac patch was as effective as diclofenac injection but at the same time administration of patch is devoid of pain, local side effects, drug destruction by stomach & digestive enzymes and first pass metabolism in liver. Conclusions: Inspite of so many advantages being offered by patch, its use in routine practice is not so common. Probably it is due to lack of awareness and a mental inertia to accept a new concept among medical professionals. This issue needs to be addressed by continuous usage of it by the people who are familiar with its use and popularising it among others.