Rate Of Gastrointestinal Absorption Research Articles

FDA and EMA Oversight of Disruptive Science on Application of Finite Absorption Time (F.A.T.) Concept in Oral Drug Absorption: Time for Scientific and Regulatory Changes.

Background: It has been demonstrated that the concept of infinite absorption time, associated with the absorption rate constant, which drives a drug's gastrointestinal absorption rate, is not physiologically sound. The recent analysis of oral drug absorption data based on the finite absorption time (F.A.T.) concept and the relevant physiologically based finite-time pharmacokinetic (PBFTPK) models developed provided a better physiologically sound description of oral drug absorption. Methods: In this study, we re-analyzed, using PBFTPK models, seven data sets of ketoprofen, amplodipine, theophylline (three formulations), and two formulations (reference, test) from a levonorgestrel bioequivalence study. Equations for one-compartment-model drugs, for the estimation of fraction of dose absorbed or the bioavailable fraction exclusively from oral data, were developed. Results: In all cases, meaningful estimates for (i) the number of absorption stages, namely, one for ketoprofen and the levonorgestrel formulations, two for amlodipine, the immediate-release theophylline formulation, and the extended-release Theotrim formulation, and three for the extended-release Theodur formulation, (ii) the duration of each absorption stage and the corresponding drug input rate, and (iii) the total duration of drug absorption, which ranged from 0.75 h (ketoprofen) to 11.6 h for Theodur were derived. Estimates for the bioavailable fraction of ketoprofen and two theophylline formulations exhibiting one-compartment-model kinetics were derived. Conclusions: This study provides insights into the detailed characteristics of oral drug absorption. The use of PBFTPK models in drug absorption analysis can be leveraged as a computational framework to discontinue the perpetuation of the mathematical fallacy of classical pharmacokinetic analysis based on the absorption rate constant as well as in the physiologically based pharmacokinetic (PBPK) studies and pharmacometrics. The present study is an additional piece of evidence for the scientific and regulatory changes required to be implemented by the regulatory agencies in the not-too-distant future.

Tyrosine phenol-lyase inhibitor quercetin reduces fecal phenol levels in mice.

Tyrosine phenol-lyase (TPL), which is expressed in intestinal bacteria, catalyzes the formation of phenol from the substrate L-Tyr. Bacterial metabolite phenol and the sulfate conjugate (phenyl sulfate) are known as a type of uremic toxins, some of which exert cytotoxicity. Therefore, pathologically elevated phenol and phenyl sulfate levels are strongly implicated in the etiology and outcome of uremia. In this study, we explored the inhibitory effects of dietary polyphenols on TPL-catalyzed phenol production using a TPL activity assay. Quercetin, one of the most popular polyphenols, exhibited the strongest inhibitory activity (Ki = 19.9 µM). Quercetin competitively inhibited TPL, and its activity was stronger than that of a known TPL inhibitor (Tyr analog; 2-aza-Tyr, Ki = 42.0 µM). Additionally, quercetin significantly inhibited phenol production in TPL-expressing bacterial cultures (Morganella morganii and Citrobacter koseri) and Tyr-rich (5%) diet-fed C57BL/6J mouse feces. Our findings suggest that quercetin is the most promising polyphenol for reducing phenol levels. Because quercetin has a low gastrointestinal absorption rate, TPL inhibition in the intestinal tract by quercetin may be an effective strategy for treating uremia.

Determination of trace elements and electrolyte levels in kidney tissue of simvastatin-treated septic rats.

Trace elements are cofactors in various enzymes in the antioxidant defense and cell homeostasis required in the tissue during inflammation. In acute kidney injury induced by lipopolysaccharide (LPS), renal cells are affected by cytotoxicity. Renal evacuation and gastrointestinal absorption rates are important in regulating plasma levels of trace elements. Simvastatin is a widely used anti-lipidemic drug with known anti-inflammatory effects. This study aimed to examine the effect of simvastatin on trace elements and electrolyte levels in kidney tissue in rats with LPS-induced sepsis. Adult male Wistar albino rats were divided into four groups: control, LPS (20mg/kg, i.p., single dose), simvastatin (20mg/kg, o.p., 5days), and LPS + Simvastatin (LPS + Sim). Sodium, potassium, calcium, magnesium, selenium, zinc, copper, and histological structural changes were examined in kidney tissue samples 4h after LPS execution. The inductively coupled plasma optical emission spectroscopy technique (ICP-OES) was used to determine the tissue trace element levels. In rats with sepsis-induced LPS, selenium, calcium, sodium, and magnesium levels significantly decreased while copper, potassium, and zinc levels significantly increased compared to other experimental groups. In sepsis treated with the simvastatin (LPS + Simvastatin) group, trace elements and electrolyte levels are like the control groups, apart from selenium levels. Selenium levels were significantly decreased in the LPS + Simvastatin group compared to the controls. As a result of examining the kidney tissues under a light microscope, simvastatin improved tissue damage caused by LPS-induced acute kidney injury. LPS-induced renal injury and simvastatin caused significant changes in the oxidant/antioxidant system. In septic rats, simvastatin was shown to balance some trace element levels, and it may improve damage in the kidney tissue.

Novel computational and drug design strategies for inhibition of monkeypox virus and Babesia microti: molecular docking, molecular dynamic simulation and drug design approach by natural compounds.

The alarming increase in tick-borne pathogens such as human Babesia microti is an existential threat to global public health. It is a protozoan parasitic infection transmitted by numerous species of the genus Babesia. Second, monkeypox has recently emerged as a public health crisis, and the virus has spread around the world in the post-COVID-19 period with a very rapid transmission rate. These two novel pathogens are a new concern for human health globally and have become a significant obstacle to the development of modern medicine and the economy of the whole world. Currently, there are no approved drugs for the treatment of this disease. So, this research gap encourages us to find a potential inhibitor from a natural source. In this study, a series of natural plant-based biomolecules were subjected to in-depth computational investigation to find the most potent inhibitors targeting major pathogenic proteins responsible for the diseases caused by these two pathogens. Among them, most of the selected natural compounds are predicted to bind tightly to the targeted proteins that are crucial for the replication of these novel pathogens. Moreover, all the molecules have outstanding ADMET properties such as high aqueous solubility, a higher human gastrointestinal absorption rate, and a lack of any carcinogenic or hepatotoxic effects; most of them followed Lipinski's rule. Finally, the stability of the compounds was determined by molecular dynamics simulations (MDs) for 100 ns. During MDs, we observed that the mentioned compounds have exceptional stability against selected pathogens. These advanced computational strategies reported that 11 lead compounds, including dieckol and amentoflavone, exhibited high potency, excellent drug-like properties, and no toxicity. These compounds demonstrated strong binding affinities to the target enzymes, especially dieckol, which displayed superior stability during molecular dynamics simulations. The MM/PBSA method confirmed the favorable binding energies of amentoflavone and dieckol. However, further in vitro and in vivo studies are necessary to validate their efficacy. Our research highlights the role of Dieckol and Amentoflavone as promising candidates for inhibiting both monkeypox and Babesia microti, demonstrating their multifaceted roles in the control of these pathogens.

Evaluating the Impact of Vitamin E Treatment on Paraquat Induced Toxicity in Liver

Paraquat is a weed destroyer utilized by agriculturists to safeguard their harvests against weed and increase crop yields. Paraquat has high gastrointestinal absorption rate and being very poisonous, it harms the liver, kidney, and the lungs by delivering free radicals, NF-KB activation, and apoptosis in numerous cells. The experimental study used. The average weight of 200 male Wistar rats was 200±20g. The two hundred rats were divided into four groups of fifty. The groups were labelled as A, B, C, and D. A control group received no paraquat, while groups B, C, and D received either 0.02g, 0.04g, or 0.06g of paraquat per kilogramme of rat every two weeks for three months. Each group consisted of two smaller groups. There were subgroups "A0" and "AVE" within the "A" group, "B0" and "BVE" within the "B" group, "C0" and "CVE" within the "C" group, and "D0" and "DVE" within the "D" group. Subgroups "A0," "B0," "C0," and "D0" did not receive vitamin E, while those in "AVE," "BVE," "CVE," and "DVE" did. subgroups weekly for one month after paraquat chronic treatment. Blood was acquired and assayed for liver function test. Aside from A0 grounp which is the control group, B0, C0, and D0 being the test groups (paraquat treated groups) as well as the BVE, CVE, and DVE vit. E treatment subgroups had a measurably significant difference, p-value≤0.05, in SGOT, SGPT, ALP, and GGT, a result which affirmed the toxic potential of paraquat and the ameliorative impact of vit. E. The outcomes showed that vitamin E treatment is strong against paraquat instigated liver toxicity on a one month weekly treatment plan.

Plant-Based Meat Analogues from Alternative Protein: A Systematic Literature Review.

This study aimed to conduct a systematic literature review (SLR) of the research performed in the plant-based meat analogues area. Historical, current, and future tendencies are discussed. The paper offers a comprehensive SLR coupled with a bibliometric analysis of the publication from 1972 to January 2022. The articles were obtained using a research string and precise inclusion and exclusion criteria from two prominent databases, Scopus and Web of Science (WoS). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow technique was used to describe the data screening and selection. In total, 84 publications were selected for further analysis after a thorough literature assessment. From this study, six main themes were identified: (1) objectives of the study; (2) type of plant protein; (3) product type; (4) added ingredients; (5) texturization technique; and (6) quality assessment considered in the studies. Recent trends in publication imply that meat analogue technology is gaining prominence. This review revealed significant research on improving meat analogues via texturization. Even though extrusion is used industrially, the technique is still in its infancy and needs improvement. Future studies should focus more on fiber and protein–protein interactions, macromolecule conformation and mechanisms, diversifying or improving current methods, sensory attributes, and gastrointestinal absorption rate of each novel protein ingredient.

Development of a population pharmacokinetic/pharmacodynamic model for various oral paclitaxel formulations co-administered with ritonavir and thrombospondin-1 based on data from early phase clinical studies

PurposeOrally administered paclitaxel offers increased patient convenience while providing a method to prolong exposure without long continuous, or repeated, intravenous infusions. The oral bioavailability of paclitaxel is improved through co-administration with ritonavir and application of a suitable pharmaceutical formulation, which addresses the dissolution-limited absorption of paclitaxel. We aimed to characterize the pharmacokinetics of different paclitaxel formulations, co-administered with ritonavir, and to investigate a pharmacodynamic relationship between low-dose metronomic (LDM) treatment with oral paclitaxel and the anti-angiogenic marker thrombospondin-1 (TSP-1).MethodsFifty-eight patients treated with different oral paclitaxel formulations were included for pharmacokinetic analysis. Pharmacodynamic data was available for 36 patients. All population pharmacokinetic/pharmacodynamic modelling was performed using non-linear mixed-effects modelling.ResultsA pharmacokinetic model consisting of gut, liver, central, and peripheral compartments was developed for paclitaxel. The gastrointestinal absorption rate was modelled with a Weibull function. Relative gut bioavailabilities of the tablet and capsule formulations, as fractions of the gut bioavailability of the drinking solution, were estimated to be 0.97 (95%CI: 0.67–1.33) and 0.46 (95%CI: 0.34–0.61), respectively. The pharmacokinetic/pharmacodynamic relationship between paclitaxel and TSP-1 was modelled using a turnover model with paclitaxel plasma concentrations driving an increase in TSP-1 formation rate following an Emax relationship with an EC50 of 284 ng/mL (95%CI: 122–724).ConclusionThe developed pharmacokinetic model adequately described the paclitaxel plasma concentrations for the different oral formulations co-administered with ritonavir. This model, and the established pharmacokinetic/pharmacodynamic relationship with TSP-1, may facilitate future development of oral paclitaxel.

Advancement of nanomedicines in chronic inflammatory disorders.

Chronic diseases, as stated by the WHO, are a threat to human health which kill 3 out of every 5 people worldwide. Therapeutics for such illnesses can be developed using traditional medicine. However, it is not an easy path from natural products to Western pharmacological and pharmaceutical methods. For several decades, chronic inflammatory disorders, especially in Westernized countries, have increased incidence and prevalence. Several NSAIDs are used to decrease inflammation and pain; however, there are numerous negative consequences of these anti-inflammatory medications, whereas plant-based natural products have anti-inflammatory therapeutic benefits that have little or no adverse effects. Nanoparticles are a new type of drug delivery device that may be designed to provide excellent target selectivity for certain cells and tissues while also having a high drug loading capacity, resulting in better pharmacokinetics, pharmacodynamics (PKPD), and therapeutic bioavailability. The size and polarity of phytochemical compounds make it hard to pass the blood–brain barrier (BBB), blood-vessel endothelial lining, gastrointestinal tract and mucosa. In addition, the gastrointestinal system is enzymatically destroyed. Therefore, nanoparticles or nanocrystals might also be used for encapsulation or conjugation of these chemicals as a method to improve their organic effectiveness through their gastrointestinal stability, absorption rate and dispersion. The therapy of numerous inflammatory illnesses, including arthritis, gastritis, Nephritis, Hepatitis (Type A, B &C), ulcerative colitis, Alzheimer's disease, atherosclerosis, allergic responses (asthma, eczema) or autoimmune disorders, is characterised by nanoparticles. This review paper provides information on the numerous nanosystem described with their probable mechanism to treat chronic inflammatory diseases.

A predictive toolset for the identification of degradation pattern and toxic hazard estimation of multimeric hazardous compounds persists in water bodies

An array of industrial processing units generates many multimeric hazardous compounds, such as complex technical lignin and its toxic derivatives, thereby persist in expelled water bodies. The inclusion of some group of motifs in the complex technical lignin structure helps it resist degrade biologically, most often even recalcitrant. Relatively small concentrations of lignin are harmful to aquatic organisms and can trigger environmental hazards. Sadly, the entire biotransformation pathway and insightful information about these toxic derivatives are incomplete and missing in the literature. This is mainly because the current conventional treatments often fail to identify all transformed compounds and their environmental fate. Thus, a robust toolset is much needed to cover this literature gap. Inadequate performance of conventional remediation processes and biological degradation patterns can be maximally optimized with the aid of predictive toolset methods that could offer better degradability and complete transformed compound information. A predictive toolset-assisted biodegradation pattern determination is a multifaceted and reliable analytical technique that can help to overcome existing shortcomings by providing an entire transformation pathway. Considering the above critiques, this work reports on the degradation pattern, and toxicological endpoints of five hazardous compounds, i.e., 2-chlorosyringaldehyde, 5-chlorovanillin, catechol, guaiacyl 4-O-5 guaiacyl, and syringyl β-O-4 syringyl β-O-4 sinapyl alcohol, that persists in water matrices. The predictive transformation pattern was revealed notably less complex end-products of catechol as; succinate, and 2-Oxo-4-pentenoate. The gastrointestinal (GI) absorption rate was found high for all tested compounds, excluding trimer compound, i.e., syringyl β-O-4 syringyl β-O-4 sinapyl alcohol. The toxicity and persistence profile tested via Toxtree showed that the Cramer Rules, Verhaar Scheme, and Structural Alerts for Reactivity, (START) biodegradation ability as positive, and all five target compounds were found as class-II persistent compounds. Furthermore, the Ecological Structure-Activity Relationships (ECOSAR)assisted testing specifies that all tested derivatives have multiple aquatic toxic levels. In summary, the current findings endorse the hazardous compounds and undertake prescreening of the deprivation policy to protect the environment.

Nasal Delivery of Acute Medications for Migraine: The Upper Versus Lower Nasal Space.

The acute treatment of migraine requires effective drugs that are well tolerated and provide rapid and consistent pain relief. Oral tablets are the most commonly used acute treatment for migraine; however, their effectiveness is limited by the rate of gastrointestinal (GI) tract absorption and first-pass hepatic metabolism, and they may not be ideal for patients experiencing GI motility issues. Nasal delivery is an attractive alternative route as it may circumvent GI tract absorption, avoid first-pass metabolism in the liver, and potentially reduce the frequency of GI adverse events. The large surface area and high vascularity within the nose may permit rapid absorption of therapeutics into the systemic circulation, allowing for rapid onset of action. However, the site of drug deposition (upper versus lower nasal cavity) may influence drug pharmacokinetics. Most approved nasal migraine therapies target the lower nasal space where the epithelium is less permeable, and they may be quickly cleared away due to increased ciliary function or dripping from the nose or swallowing, resulting in variable absorption and limited bioavailability. Together with its abundant vascularization, relative mucosal thickness stability, and low clearance rates, the upper nasal space harnesses the benefits of nasal delivery to potentially maximize drug efficacy.

The Pharmacokinetics of Sildenafil May Be Affected by Intestinal Absorption Rate in Children Admitted to the Intensive Care Unit.

This study was performed for a better understanding of the pharmacokinetics of sildenafil (SIL) and N-desmethyl sildenafil (DMS) in 13 children treated in the intensive care unit (ICU). Blood samples were taken periodically after the first oral administration of SIL (0.5 mg/kg). Plasma concentrations were analyzed by tandem LC/MS. Of the 13 patients, apparent peaks in the plasma concentration of SIL were observed in four patients, with the other nine patients showing reduced or delayed drug absorption of SIL. The maximum plasma concentrations of SIL after administration varied in range from 7.8 to 101.0 ng/mL. The parent drug-to-metabolite (SIL/DMS) ratios of the nine patients with reduced or delayed drug absorption of SIL were relatively lower than those in the four patients with rapid absorption of the drug. These observations suggested that the inter-individual variability of intestinal absorption and/or first-pass extraction of SIL was involved in the pharmacokinetic variability of the drug. Next, we evaluated the impact of changes in the gastrointestinal absorption rate on the pharmacokinetics of the drug. That is, SIL (2.5 mg/body) was administered at two different rates in the duodenum of rats. When SIL was administered for 10 min, the Cmax and bioavailability were 3.46 ± 1.65 µg/mL and 23.2 ± 11.1%, respectively. When SIL was administered for 60 min, the Cmax and bioavailability were 0.990 ± 0.352 µg/mL and 9.91 ± 3.79%, respectively. These findings suggest that the drug absorption rate was at least partly responsible for the pharmacokinetic variability of SIL in the ICU children.

Improved Prediction of the Drug-Drug Interactions of Pemafibrate Caused by Cyclosporine A and Rifampicin via PBPK Modeling: Consideration of the Albumin-Mediated Hepatic Uptake of Pemafibrate and Inhibition Constants With Preincubation Against OATP1B

Pemafibrate (PMF) is highly albumin-bound (>99.8%) and a substrate for hepatic uptake transporters (OATP1B) and CYP enzymes. Here, we developed a PBPK model of PMF to capture drug-drug interactions (DDI) incurred by cyclosporine (CsA) and rifampicin (RIF), the two OATP1B inhibitors. Initial PBPK modeling of PMF utilized in vitro hepatic uptake clearance (PSinf) obtained in the absence of albumin, but failed in capturing the blood PMF pharmacokinetic (PK) profiles. Based on the results that in vitro PSinf of unbound PMF was enhanced in the presence of albumin, we applied the albumin-facilitated dissociation model and the resulting PSinf parameters improved the prediction of the blood PMF PK profiles. In refining our PBPK model toward improved prediction of the observed DDI data (PMF co-administered with single dosing of CsA or RIF; PMF following multiple RIF dosing), we adjusted the previously obtained in vivo OATP1B inhibition constants (Ki,OATP1B) of CsA or RIF for pitavastatin by correcting for substrate-dependency. We also incorporated the induction of OATP1B and CYP enzymes after multiple RIF dosing. Sensitivity analysis informed that the higher gastrointestinal absorption rate constant could further improve capturing the observed DDI data, suggesting the possible inhibition of intestinal ABC transporter(s) by CsA or RIF.

Gastrointestinal Absorption Rate in Rats for Radiocesium in Soil Collected near Fukushima Power Plant or Doped Artificially with <sup>134</sup>CsCl

Gastrointestinal Absorption Rate in Rats for Radiocesium in Soil Collected near Fukushima Power Plant or Doped Artificially with <sup>134</sup>CsCl

HYGIENIC EVALUATION OF THE QUALITY OF DRINKING WATER AND RISKS FOR THE HEALTH OF THE POPULATION OF THE PRIMORYE TERRITORY

Ntroduction. The assessment of water quality and safety of centralized water supply systems in the Primorsky Krai was carried out in order to assess hygiene levels of public health risks associated with drinking water from the distribution network. Material and methods. The data of laboratory studies on sanitary and chemical parameters in drinking water of the distribution network of the Primorsky region were used. Hygienic assessment of drinking water was carried out according to regulatory requirements, the effect of summation of biological effect was calculated. The work used methodological recommendations for calculating the index of chemical water pollution and the utility coefficient, as well as a guide for assessing the health risks of the population when exposed to chemicals of a non-carcinogenic and carcinogenic nature. Non-carcinogenic and carcinogenic risks were calculated for all potable water of centralized water supply based on the average daily intake dose and the reference dose of chemicals supplied with drinking water. The risk profile for carcinogenic and non-carcinogenic effects was achieved by comparing exposure levels with reference concentrations (safe) for human health. The risk profile for the combined effects of chemical compounds is based on the calculation of the hazard index (HI). A study on carcinogenic risk was carried out for substances that are identified as carcinogens according to the classification of an international agency for the study of cancer. For the analysis and statistical processing of information, the program "MS Excel" was used. Results. An assessment of the sanitary and epidemiological safety of centralized systems of domestic and drinking water supply in the region showed that the highest contribution to poor health is made by the content of arsenic, nitrates, iron, silicon, and petroleum products in drinking water. According to the values of hazard indices, the skin and mucous membranes, the central nervous system, the immune system, the endocrine system, the circulatory and digestive organs are exposed to adverse effects from chemicals in drinking water. The individual carcinogenic risk ranges from negligibly small to the upper limit of acceptable carcinogenic risk. Assessment of the potable water value indicator revealed a deficit situation in calcium, sodium, fluorine and general mineralization of water. The risk assessment for arsenic, tetrachlorethylene, and chloroform, which have carcinogenic properties and are the most important pollutants of drinking water, has shown that the individual risk levels for these substances are within the first and second ranges, which corresponds to the allowable and maximum allowable risk. Discussion. Arsenic concentration in adults was found to be not detected with risks greater than one, while for children, the non-carcinogenic risk from arsenic exceeded the level of safe exposure (HQ> 1), because children are more susceptible to toxic substances due to their relatively large volume of respiration and the rate of gastrointestinal absorption (due to greater permeability of the intestinal epithelium), and also due to the immature system of detoxification enzymes and a relatively lower rate of excretion of toxic chemicals. According to the level of non-carcinogenic risk for children, nitrates follow arsenic. Nitrates have a hypoxic effect, increasing the concentration of the irreversible form of hemoglobin - methemoglobin. The toxicity of nitrates is related to their transformation into the human body into nitrosamines. As a result, the child's organism responds more sharply than in adults to the presence of chemicals in the water. The general mineralization of drinking water is one of the integral index of the quality of drinking water. Calcium and magnesium deficiency can be an independent risk factor for the development of various diseases and manifest pathologies of the cardiovascular system: coronary heart disease, hypertensive disease, myocardial infarction, etc. The tap water is known to be is not overloaded with carbonates, since they can lead to spoilage of water pipes. Therefore, to enrich the water with calcium and magnesium, the technology of creating bottled water uses mineral additives, which means that such water can become an additional source of minerals. Conclusion. Sanitary and hygienic assessment of centralized systems of domestic and drinking water supply in the Primorsky Territory has shown that the quality of drinking water depends on the concentration of arsenic, nitrates, iron, silicon and petroleum products. It should be noted that with the daily use of water from the distribution network throughout life, the likelihood of developing harmful effects on the health of adults and children is insignificant.

Effect on the Gastrointestinal Absorption of Drugs from Different Classes in the Biopharmaceutics Classification System, When Treating with Liraglutide

Like other GLP-1 receptor agonists used for treatment of type 2 diabetes, liraglutide delays gastric emptying. In this clinical absorption study, the primary objective was to investigate the effect of liraglutide (at steady state) on the rate and/or extent of gastrointestinal (GI) absorption of concomitantly orally taken drugs from three classes of the Biopharmaceutics Classification System (BCS). To provide a general prediction on liraglutide drug-drug absorption interaction, single-dose pharmacokinetics of drugs representing BCS classes II (low solubility-high permeability; atorvastatin 40 mg and griseofulvin 500 mg), III (high solubility-low permeability; lisinopril 20 mg), and IV (low solubility-low permeability; digoxin 1 mg) were studied in healthy subjects at steady state of liraglutide 1.8 mg, or placebo, in a two-period crossover design. With liraglutide, the oral drugs atorvastatin, lisinopril, and digoxin showed delayed tmax (by ≤2 h) and did not meet the criterion for bioequivalence for Cmax (reduced Cmax by 27-38%); griseofulvin had similar tmax and 37% increased Cmax. Although the prespecified bioequivalence criterion was not met by all drugs, the overall plasma exposure (AUC) of griseofulvin, atorvastatin, lisinopril, and digoxin only exhibited minor changes and was not considered to be of clinical relevance.

Phytochemicals in Japanese plums: impact of maturity and bioaccessibility

In recent years there has been increasing consumer interest in the potential health benefits of dietary derived phytochemicals such as polyphenols (including anthocyanins and flavonols) and carotenoids. A new variety of Japanese plum (Prunus salicina Lindl.), named Queen Garnet (QG), was developed as a high anthocyanin plum in a Queensland (Australia) Government breeding program and may be attractive to consumers, but knowledge of other phytochemical content, and bioaccessibility, is currently limited. As a result, the present study examined (1) the impact of harvest date on anthocyanins, quercetin glycosides and carotenoids in Queen Garnet and another red fleshed commercial Japanese plum variety, Black Diamond (BD), (2) the content of bound phenolics in plum fruit and (3) the in vitro bioaccessibility and release of these phytochemicals as an initial measure to predict their potential bioavailability. For both QG and BD, the last harvest resulted in the highest anthocyanin content in peel, flesh and whole fruit, whereas no significant effects could be observed for quercetin glycosides, and total carotenoids decreased over time. The highest content of bound phenolics (30% of total amount) could be found in BD flesh. Between 53% and 59% of quercetin glycosides and anthocyanins were released from QG after the gastric and small intestinal digestion procedure, whereas the release of carotenoids ranged between 4–6%. A relative high release of anthocyanins and quercetin glycosides could be observed from QG which may result in a higher gastro-intestinal absorption rate of these compounds. However, follow-up studies (clinical trials) are warranted to investigate the in vivo bioavailability and subsequently biological activity of QG.

Refined biokinetic model for humans exposed to cobalt dietary supplements and other sources of systemic cobalt exposure

An updated biokinetic model for human exposures to cobalt (Co) was developed based on a comprehensive set of human pharmacokinetics data collected from five male and five female volunteers who ingested ∼1mgCo/day of a Co supplement for 3months. Three key experimental observations from the human dosing studies were incorporated into the model: (1) an increase in the measured fraction of large molecular serum protein bound Co from 95% during dosing to 99% after dosing; (2) a linear decrease in Co red blood cell concentration after dosing; and (3) Co renal clearance consistent with estimated glomerular filtration rates and free Co2+ concentration. The model was refined by adding compartments accounting for (1) albumin bound Co in intravascular fluid (serum); (2) albumin bound Co in extravascular fluid with physiologic exchange rates of albumin bound Co between extravascular and intravascular fluid; and (3) a novel sequential cascade of compartments representing red blood cell ages between 1 and 120days. Reasonable agreement between the modeled and measured urine, serum, and whole blood concentrations were observed (r>0.84, slope=0.79–1.0) with gastrointestinal absorption rates between 9% and 66%. In addition, model predictions agreed well with data from several external studies representing healthy human volunteers, dialysis patients, anephric patients, a Co-poisoning incident and whole body retention studies. Our revised model considerably improves the state of knowledge on human Co kinetics, and should be helpful for evaluating elevated blood Co concentrations in currently exposed populations, such as metal-on-metal (MoM) hip implant patients.

Human in Vivo Regional Intestinal Permeability: Importance for Pharmaceutical Drug Development

Both the development and regulation of pharmaceutical dosage forms have undergone significant improvements and development over the past 25 years, due primarily to the extensive application of the biopharmaceutical classification system (BCS). The Biopharmaceutics Drug Disposition Classification System, which was published in 2005, has also been a useful resource for predicting the influence of transporters in several pharmacokinetic processes. However, there remains a need for the pharmaceutical industry to develop reliable in vitro/in vivo correlations and in silico methods for predicting the rate and extent of complex gastrointestinal (GI) absorption, the bioavailability, and the plasma concentration-time curves for orally administered drug products. Accordingly, a more rational approach is required, one in which high quality in vitro or in silico characterizations of active pharmaceutical ingredients and formulations are integrated into physiologically based in silico biopharmaceutics models to capture the full complexity of GI drug absorption. The need for better understanding of the in vivo GI process has recently become evident after an unsuccessful attempt to predict the GI absorption of BCS class II and IV drugs. Reliable data on the in vivo permeability of the human intestine (Peff) from various intestinal regions is recognized as one of the key biopharmaceutical requirements when developing in silico GI biopharmaceutics models with improved predictive accuracy. The Peff values for human jejunum and ileum, based on historical open, single-pass, perfusion studies are presented in this review. The main objective of this review is to summarize and discuss the relevance and current status of these human in vivo regional intestinal permeability values.

Effects of Dietary Trans Fatty Acids on Fat Accumulation and Metabolic Rate in Rat

Dietary intake of high trans-fatty acids (TFAs) is well known to increase the risk of cardiovascular diseases. However, few reports demonstrated definitive relationships between dietary TFAs and obesity. In addition, the difference in the gastrointestinal absorption rate of TFAs containing oil from that of cis-FAs containing oil was not taken into consideration in many rat studies. In experiment A, we investigated the difference in the apparent absorption rate of TFAs containing oil from control oil. Hydrogenated rapeseed oil and a mixture of camellia oil and tristearin (90:10 [w/w]) were used as TFA-containing test oil and control oil, respectively. Ten Wistar rats were divided into the control group or TFA group, and fed the respective diet containing the control oil or the test oil for 1 week. The apparent absorption rates of these oils were measured by fecal fat excretion rate and dietary fat intake. The results showed a significantly lower gastrointestinal apparent absorption rate of the test oil (93.1%) than that of the control oil (96.2%). In consideration of the apparent absorption rate of these dietary oils, the effects of dietary TFAs on body fat accumulation and energy metabolism were investigated in rats. Twenty-eight Wistar rats were divided into the control group or the TFA group. Each group received an isoenergetic diet containing the control oil or the test oil for 8 weeks. Pre- and postprandial metabolic rates were measured between weeks 7 and 8. The test oil-based diet did not significantly influence body weight gain, fat accumulation, and metabolic rate. In contrast, liver weight, hepatic triglyceride content, and serum non-high density lipoprotein (HDL)-cholesterol (CHO)/HDL-CHO ratio were significantly higher in the TFA group than in the control group. In conclusion, these findings suggest that dietary TFAs did not influence body fat accumulation but increased the levels of risk markers of cardiovascular diseases.

Toxicity and Fate of Heavy Metals with Particular Reference to Developing Foetus

Heavy metals especially lead, mercury, cadmium, arsenic and chromium are well known for causing birth defects. Although, the mother may be unaffected and unaware of the contamination, infants exposed to such agents in-utero may have a number of side effects as these substances readily move across the placental barrier. Heavy metals are dangerous because they have the tendency to bioaccumulate in biological organisms over a period of time. The foetus and newborns are much more sensitive to the effects at low levels of metal exposure and this is mainly due to body weight being less and higher rate of food consumption rate, higher gastrointestinal absorption rate, less effective renal excretion, and a less effective blood-brain barrier. On the other hand, lead is tightly bound to red blood cells, thereby enhancing the transfer from maternal circulation through the placenta to the foetus. Placental transfer begins as early as the twelfth week of gestation. Arsenic is found in drinking water and is a potent toxicant but scanty research has been done on its effect on maternal health. Chromium (Cr 6+ ) accumulates in placenta and impairs foetal development in the placenta. Therefore, the fertile population should prevent themselves from exposure to chemicals, drugs and other environmental agents.