Pharmacokinetics of intranasal drugs, still a missed opportunity?

The intranasal (IN) route of administration is important for topical drugs and drugs intended to act systemically. More recently, direct nose-to-brain input was considered to bypass the blood-brain barrier.Processes related to IN absorption and nose-to-brain distribution are complex and depend, sometimes in contrasting ways, on chemico-physical and structural parameters of the compounds, and on formulation options.Due to the intricacies of these processes and despite the large number of articles published on many different IN compounds, it appears that absorption after IN dosing is not yet fully understood. In particular, at variance of the understanding and modelling approaches that are available for predicting the pharmacokinetics (PK) following oral administration of xenobiotics, it appears that there is not a similar understanding of the chemico-physical and structural determinants influencing drug absorption and disposition of compounds after IN administration, which represents a missed opportunity for this research field. This is even more true regarding the understanding of the direct nose-to-brain input. Due to this, IN administrations may represent an interesting and open research field for scientists aiming to develop PK property predictions tools, mechanistic PK models describing rate and extent of IN absorption, and translational tools to anticipate the clinical PK following IN dosing based on in vitro and in vivo non clinical experiments.This review intends to provide: i) some basic knowledge related to the physiology of PK after IN dosing, ii) a non-exhaustive list of preclinical and clinical examples related to compounds explored for the potential nose-to-blood and nose-to-brain passage, and iii) the identification of some areas requiring improvements, the understanding of which may facilitate the development of IN drug candidates.

In Vitro Human Cell-Based Experimental Models for the Evaluation of Enteric Metabolism and Drug Interaction Potential of Drugs and Natural Products.

Elements of key enteric drug metabolism and disposition pathways are reviewed to aid the assessment of the applicability of current cell-based enteric experimental systems for the evaluation of enteric metabolism and drug interaction potential. Enteric nuclear receptors include vitamin D receptor, constitutive androstane receptor, pregnane X receptor, farnesoid X receptor, liver X receptor, aryl hydrocarbon receptor, and peroxisome proliferator-activated receptor. Enteric drug metabolizing enzyme pathways include both cytochrome P450 (P450) and non-P450 drug metabolizing enzymes based on gene expression, proteomics, and activity. Both uptake and efflux transporters are present in the small intestine, with P-glycoprotein found to be responsible for most drug-drug and food-drug interactions. The cell-based in vitro enteric systems reviewed are 1) immortalized cell line model: the human colon adenocarcinoma (Caco-2) cells; 2) human stem cell-derived enterocyte models: stem cell enteric systems, either from intestinal crypt cells or induced pluripotent stem cells; and 3) primary cell models: human intestinal slices, cryopreserved human enterocytes, permeabilized cofactor-supplemented (MetMax) cryopreserved human enterocytes, and cryopreserved human intestinal mucosa. The major deficiency with both immortalized cell lines and stem cell-derived enterocytes is that drug metabolizing enzyme activities, although they are detectable, are substantially lower than those for the intestinal mucosa in vivo. Human intestine slices, cryopreserved human enterocytes, MetMax cryopreserved human enterocytes, and cryopreserved human intestinal mucosa retain robust enteric drug metabolizing enzyme activity and represent appropriate models for the evaluation of metabolism and metabolism-dependent drug interaction potential of orally administered xenobiotics including drugs, botanical products, and dietary supplements. SIGNIFICANCE STATEMENT: Enteric drug metabolism plays an important role in the bioavailability and metabolic fate of orally administered drugs as well as in enteric drug-drug and food-drug interactions. The current status of key enteric drug metabolism and disposition pathways and in vitro human cell-based enteric experimental systems for the evaluation of the metabolism and drug interaction potential of orally administered substances is reviewed.

In Silico Simulation of Simultaneous Percutaneous Absorption and Xenobiotic Metabolism: Model Development and a Case Study on Aromatic Amines.

PURPOSE: To advance physiologically-based pharmacokinetic modelling of xenobiotic metabolism by integrating metabolic kinetics with percutaneous absorption. METHOD: Kinetic rate equations were proposed to describe the metabolism of a network of reaction pathways following topical exposure and incorporated into the diffusion-partition equations of both xenobiotics and metabolites. The published ex vivo case study of aromatic amines was simulated. Diffusion and partition properties of xenobiotics and subsequent metabolites were determined using physiologically-based quantitative structure property relationships. Kinetic parameters of metabolic reactions were best fitted from published experimental data. RESULTS: For aromatic amines, the integrated transdermal permeation and metabolism model produced data closely matched by experimental results following limited parameter fitting of metabolism rate constants and vehicle:water partition coefficients. The simulation was able to produce dynamic concentration data for all the dermal layers, as well as the vehicle and receptor fluid. CONCLUSION: This mechanistic model advances the dermal in silico functionality. It provides improved quantitative spatial and temporal insight into exposure of xenobiotics, enabling the isolation of governing features of skin. It contributes to accurate modelling of concentrations of xenobiotics reaching systemic circulation and additional metabolite concentrations. This is vital for development of both pharmaceuticals and cosmetics.

Impact of stressors in the aviation environment on xenobiotic dosimetry in humans: physiologically based prediction of the effect of +Gz-forces.

The application of physiologically based modeling approaches in evaluating health risks in diverse environments is limited by scarcity of comprehensive reviews detailing how physiological parameters are altered due to stressors. A modern high-performance aviation environment in particular has the potential for simultaneous exposure to chemical and non-chemical stressors which may interact via non-chemical stressor-mediated pharmacokinetic alterations. To support physiologically based pharmacokinetic (PBPK) modeling of in-flight disposition inhaled chemicals, literature review, and synthesis was conducted to determine the impact of gravitational (+Gz) forces on PBPK modeling inputs. Specifically, changes in cardiac output and related parameters heart rate and stroke volume, breathing frequency, tidal volume, and pulmonary and alveolar ventilation rate in vivo were extracted from 36 publications and related mathematically to +Gz intensity. A scenario was simulated where a pilot performing test flights might inhale organic chemicals at the occupational exposure guideline level while experiencing sustained, elevated +Gz. Peak arterial blood concentrations of 1,2,4-trimethylbenzene during a 1 h-flight at +4 Gz were predicted to increase 2-fold relative to would occur on the ground under baseline conditions. This case study demonstrates the potential value of scenario-specific physiological information in assessing changes in risk-relevant internal dosimetry, providing better information for potential risk management actions.

Metabolic profiles and pharmacokinetics of Qingre Xiaoyanning capsule, a traditional Chinese medicine prescription of Sarcandrae Herba, in rats by UHPLC coupled with quadrupole time-of-flight tandem mass spectrometry.

Qingre Xiaoyanning capsule is a famous traditional Chinese medicine prescription which consisted of Sarcandrae Herba (also named Caoshanhu in China) water extract for the frequent treatment of inflammation and immunity related diseases. Until now, the in vivo bioactive components of Qingre Xiaoyanning capsule have not yet been fully addressed. In this study, a total of 42 xenobiotics including 20 prototypes and 22 metabolites were identified in rats after oral administration of Qingre Xiaoyanning capsule using ultra-high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Subsequently, isofraxidin and rosmarinic acid, two bioactive components with high exposure in rat plasma, were quantitatively analyzed, while another 20 major absorbed components were semi-quantitatively measured, to investigate together the pharmacokinetics behavior of Qingre Xiaoyanning capsule. Taken together, this study provided comprehensive knowledge of in vivo disposal of this prescription, which could help reveal the potential bioactive components, and would be conducive to further pharmacological mechanism research as well as quality control approach improvement of Qingre Xiaoyanning capsule and Sarcandrae Herba related prescriptions.

A systematic analysis of Nrf2 pathway activation dynamics during repeated xenobiotic exposure.

Oxidative stress leads to the activation of the Nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway. While most studies have focused on the activation of the Nrf2 pathway after single chemical treatment, little is known about the dynamic regulation of the Nrf2 pathway in the context of repeated exposure scenarios. Here we employed single cell live imaging to quantitatively monitor the dynamics of the Nrf2 pathway during repeated exposure, making advantage of two HepG2 fluorescent protein reporter cell lines, expressing GFP tagged Nrf2 or sulfiredoxin 1 (Srxn1), a direct downstream target of Nrf2. High throughput live confocal imaging was used to measure the temporal dynamics of these two components of the Nrf2 pathway after repeated exposure to an extensive concentration range of diethyl maleate (DEM) and tert-butylhydroquinone (tBHQ). Single treatment with DEM or tBHQ induced Nrf2 and Srxn1 over time in a concentration-dependent manner. The Nrf2 response to a second treatment was lower than the response to the first exposure with the same concentration, indicating that the response is adaptive. Moreover, a limited fraction of individual cells committed themselves into the Nrf2 response during the second treatment. Despite the suppression of the Nrf2 pathway, the second treatment resulted in a three-fold higher Srxn1-GFP response compared to the first treatment, with all cells participating in the response. While after the first treatment Srxn1-GFP response was linearly related to Nrf2-GFP nuclear translocation, such a linear relationship was less clear for the second exposure. siRNA-mediated knockdown demonstrated that the second response is dependent on the activity of Nrf2. Several other, clinically relevant, compounds (i.e., sulphorophane, nitrofurantoin and CDDO-Me) also enhanced the induction of Srxn1-GFP upon two consecutive repeated exposure. Together the data indicate that adaptation towards pro-oxidants lowers the Nrf2 activation capacity, but simultaneously primes cells for the enhancement of an antioxidant response which depends on factors other than just Nrf2. These data provide further insight in the overall dynamics of stress pathway activation after repeated exposure and underscore the complexity of responses that may govern repeated dose toxicity.

ORGANOMETRIC CHANGES IN THYMUS UNDER THE INFLUENCE OF PROPYLENE GLYCOL.

The scientific interest in the influence of xenobiotics on the human body is due to the fact that immune organs are characterized by a pronounced response to the influence of endogenous and exogenous factors. Recently, the immunological impairment, as a manifestation of reactions to ecopathogenic conditions, suggests a major pathogenesis role in the development of cardiovascular, neuropsychiatric diseases, as well as diffuse diseases of connective tissue. Objectives - experiment was designed to elucidate the organometric changes in thymus of male rats due to impact of propylene glycol. 40 WAG matured male rats were divided randomly into two groups. The first group served as a control and constituted 8 animals. The second group of 32 rats, 8 rodents in each, were treated via gavage by aqueous solutions of propylene glycol in doze 1/10 LD50 in conversion to 26,38 g/kg during 7, 15, 30, 45 days. All animals were sacrificed on the term defined by experimental design. Thymus specimens were dissected out, and linear dimensions (length, width, height) using digital caliper were measured, along with mass and volume of the thymus. Limits of the thymus morphometric indices' variability in intact and experimental groups were calculated. The research indicates that exposure to propylene glycol caused marked organometric changes in rats' thymus. However, more pronounced changes were observed on 7th and 30th days. Were established the following limits of variability indices oscillations: IndHL of the experimental group thymus ranged from min=12.57 to max=47.54, the mean value was from 24.67 to 28.02; IndHW of the experimental group thymus ranged from min=11.96 to max=88.73, the mean value was from 36.78 to 41.41; IndT of the experimental group ranged from min = 38.17 to max=141.3, the mean value was from 71.1 to 86.52. The study of the morphometric parameters of the thymus in the experimental group of rats has established a significant reduction of all parameters and their deviation from the parameters of the control group, that shows active reaction of thymus on induced xenobiotic.

Bisphenol A exposure perturbs visual function of adult cats by remodeling the neuronal activity in the primary visual pathway.

Bisphenol A (BPA), a common environmental xenoestrogen, has been implicated in physiological and behavioral impairment, but the neuronal basis remains elusive. Although various synaptic mechanisms have been shown to mediate BPA-induced brain deficits, there are almost no reports addressing its underlying physiological mechanisms at the individual neuron level, particularly in the primary visual system. In the present study, using multiple-channel recording technique, we recorded the responses of single neurons in the primary visual system of cats to various direction stimuli both before and after BPA exposure. The results showed that the orientation selectivity of neurons in the primary visual cortex (area 17, A17) was obviously decreased after 2 h of intravenous BPA administration (0.2 mg/kg). Moreover, there were worse performances of information transmission of A17 neurons, presenting markedly decreased signal-to-noise ratio (SNR). To some extent, these functional decreases were attributable to the altered information inputs from lateral geniculate nucleus (LGN), which showed an increased spontaneous activity. Additionally, local injection of BPA (3.3 µg/ml) in A17 resulted in an obvious increase in orientation selectivity and a decrease in neuronal activity, involving enhanced activity of fast-spiking inhibitory interneurons. In conclusion, our results first demonstrate that acute BPA exposure can restrict the visual perception of cats, mainly depending on the alteration of the LGN projection, not the intercortical interaction. Importantly, BPA-induced-brain deficits might not only be confined to the cortical level but also occur as early as at the subcortical level.

Toxicity of marine pollutants on the ascidian oocyte physiology: an electrophysiological approach.

In marine animals with external fertilization, gametes are released into seawater where fertilization and embryo development occur. Consequently, pollutants introduced into the marine environment by human activities may affect gametes and embryos. These xenobiotics can alter cell physiology with consequent reduction of fertilization success. Here the adverse effects on the reproductive processes of the marine invertebrate Ciona intestinalis (ascidian) of different xenobiotics: lead, zinc, an organic tin compound and a phenylurea herbicide were evaluated. By using the electrophysiological technique of whole-cell voltage clamping, the effects of these compounds on the mature oocyte plasma membrane electrical properties and the electrical events of fertilization were tested by calculating the concentration that induced 50% normal larval formation (EC50). The results demonstrated that sodium currents in mature oocytes were reduced in a concentration-dependent manner by all tested xenobiotics, with the lowest EC50 value for lead. In contrast, fertilization current frequencies were differently affected by zinc and organic tin compound. Toxicity tests on gametes demonstrated that sperm fertilizing capability and fertilization oocyte competence were not altered by xenobiotics, whereas fertilization was inhibited in zinc solution and underwent a reduction in organic tin compound solution (EC50 value of 1.7 µM). Furthermore, fertilized oocytes resulted in a low percentage of normal larvae with an EC50 value of 0.90 µM. This study shows that reproductive processes of ascidians are highly sensitive to xenobiotics suggesting that they may be considered a reliable biomarker and that ascidians are suitable model organisms to assess marine environmental quality.

Novel functions of PXR in cardiometabolic disease.

Cardiometabolic disease emerges as a worldwide epidemic and there is urgent need to understand the molecular mechanisms underlying this chronic disease. The chemical environment to which we are exposed has significantly changed in the past few decades and recent research has implicated its contribution to the development of many chronic human diseases. However, the mechanisms of how exposure to chemicals contributes to the development of cardiometabolic disease are poorly understood. Numerous chemicals have been identified as ligands for the pregnane X receptor (PXR), a nuclear receptor functioning as a xenobiotic sensor to coordinately regulate xenobiotic metabolism via transcriptional regulation of xenobiotic-detoxifying enzymes and transporters. In the past decade, the function of PXR in the regulation of xenobiotic metabolism has been extensively studied by many laboratories and the role of PXR as a xenobiotic sensor has been well-established. The identification of PXR as a xenobiotic sensor has provided an important tool for the study of new mechanisms through which xenobiotic exposure impacts human chronic diseases. Recent studies have revealed novel and unexpected roles of PXR in modulating obesity, insulin sensitivity, lipid homeostasis, atherogenesis, and vascular functions. These studies suggest that PXR signaling may contribute significantly to the pathophysiological effects of many known xenobiotics on cardiometabolic disease in humans. The discovery of novel functions of PXR in cardiometabolic disease not only contributes to our understanding of "gene-environment interactions" in predisposing individuals to chronic diseases but also provides strong evidence to inform future risk assessment for relevant chemicals. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

Nuclear receptors and nonalcoholic fatty liver disease.

Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

Effects of selected xenobiotics on hepatic and plasmatic biomarkers in juveniles of Solea senegalensis.

In recent years, Solea senegalensis has increasingly been used in pollution monitoring studies. In order to assess its response to some particular widespread pollutants, juveniles of S. senegalensis were administered an intraperitoneal injection of the model aryl hydrocarbon receptor agonist ß-naphtoflavone (ßNF) and chemicals of environmental concern, such as the fungicide ketoconazole (KETO), the lipid regulator gemfibrozil (GEM), the surfactant nonylphenol (NP) and the synthetic hormone ethinylestradiol (EE2). Two days after injection, the effect of these chemicals was followed up as alterations of hepatic microsomal activities of the cytochrome P450 (CYPs) and associated reductases, carboxylesterases (CbEs) and the conjugation enzyme uridine diphosphate glucuronyltransferase (UDPGT). In the cytosolic fraction of the liver, the effect on CbEs, glutathione S-transferase (GST) and antioxidant activities was also considered. Alterations on the endocrine reproductive system were evaluated by plasma levels of vitellogenin (VTG) and the sex steroids estradiol (E2), testosterone (T), 11-ketotestosterone (11KT) and the progestin 17α,20ß-dihydroxy-4-pregnen-3-one (17,20ß-P). Injection with the model compound ßNF induced the hydrolysis rate of the seven CYP substrates assayed. The xenobiotic GEM induced three CYP-related activities (e.g. ECOD) and UDPGT, but depressed antioxidant defenses. EE2 induced four CYPs, more significantly ECOD and BFCOD activities. The xenoestrogens NP and EE2 altered the activities of CbE in microsomes and catalase, and were the only treatments that induced de novo VTG synthesis. In addition, the progestin 17,20ß-P, was induced in NP-injected fish. None of the treatments caused statistically significant effects on steroid plasma levels. In conclusion, the CYP substrates assayed responded specifically to treatments and juveniles of S. senegalensis appear good candidates for assessing xenobiotics exposure.

Usefulness of the chaotropic effect in sample preparation for chromatographic analysis of acidic xenobiotics in human plasma.

In this study a new RP-HPLC with photo-diode array detection method for the determination of ibuprofen ((RS)-2-(4-isobutylphenyl)propionic acid) in human plasma samples was developed. Samples were prepared by SPE and analyzed by an isocratic elution mode over a C18 column using 80% methanol. A novel sample pretreatment method, based on the addition of ionic liquids possessing chaotropic ions to small human plasma sample (100 µL), was elaborated. 1-Butyl-3-methylimidazolium chloride and 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM BF4 ) were tested from the point of view of extraction yield. Quantification was based on calibration curve applying diclofenac as the internal standard. Owing to dilution of plasma sample by 2 mM aqueous solution of BMIM BF4 before SPE, appropriate sample purification and extraction yields higher than 95% with precision lower than 2% can be achieved. Linear coefficients of correlation (r(2)) were >0.99 in the range of 0.3-5 µg/mL ibuprofen concentration in plasma. The limit of quantification was 65 ng/mL and the detection limit for ibuprofen was 19.5 ng/mL.

Metabolism and disposition of [14C]n-butyl-p-hydroxybenzoate in male and female Harlan Sprague Dawley rats following oral administration and dermal application.

n-Butyl-p-hydroxybenzoate (n-butylparaben, BPB) is an antioxidant used in foods, pharmaceuticals and cosmetics. This study investigated the disposition of ring-labelled [(14)C]BPB in Harlan Sprague Dawley rats, and in rat and human hepatocytes. BPB was rapidly cleared in hepatocytes from rat (t(1/2) = 3-4 min) and human (t(1/2) = 20-30 min). The major metabolites detected in rat hepatocytes were hydroxybenzoic acid and in human hepatocytes were hydroxybenzoic acid and hydroxyhippuric acid. [(14)C]BPB was administered to male rats orally at 10, 100 or 1000 mg/kg, intravenously at 10 mg/kg and dermally at 10 and 100 mg/kg; female rats were administered oral doses at 10 mg/kg. Oral doses of BPB were well-absorbed (>83%) and eliminated chiefly in urine (83-84%); ≤ 1% of the radioactivity remained in tissues at 24 h or 72 h after dosing. About 4% and 8%, respectively, of 100 mg/kg dermal doses were absorbed in 24 h and 72 h, and about 50% of a 10 mg/kg dose was absorbed in 72 h. Metabolites detected in urine included those previously reported, BPB-glucuronide, BPB-sulfate, hydroxybenzoic acid and hydroxyhippuric acid, but also novel metabolites arising from ring hydroxylation followed by glucuronidation and sulfation.

Styrene altered clock gene expression in serum-shocked cultured human fibroblasts.

The circadian clock can regulate the metabolic process of xenobiotics, but little is known as to circadian rhythms can be perturbed by xenobiotics. Styrene is a organic chemical widely used in occupational settings. The effects of styrene on the circadian genes of HuDE cells were evaluated after serum-shocking synchronization. A subtoxic dose of 100 µM of styrene altered the expression of clock genes BMAL1, PER2, PER3, CRY1, CRY2, and REV-ERB-α.

Ocular toxicity assessment from systemically administered xenobiotics: considerations in drug development.

The eye is a unique sensory structure, which must be evaluated for toxicity to determine the safety of drugs, industrial chemicals, and consumer products. Changes in the structure and/or function of ocular tissues following systemic administration of a potential new drug in preclinical animal models can result in significant delays in the development of a new therapeutic and in some cases lead to termination of the development. The ability to detect and characterize ocular toxicity in preclinical models and to predict risk in patients is critically dependent on the preclinical testing strategy, the availability and use of state-of-the-art ocular safety assessment tools, and the knowledge of drug mechanism of action and the current regulatory environment. This review describes the design and execution of toxicity studies with the incorporation of current methods for in vivo assessment of ocular toxicity, including methods for detecting early changes in the eye. In addition, anatomical differences among laboratory animals, preparation of globes for examination, and iatrogenic and spontaneous ocular findings are described that can affect interpretation of toxicological findings. Finally, the correlation between nonclinical outcomes and clinical evaluations is discussed in terms of expected therapeutic uses, indications, and regulatory consequences of ocular effects.

Contribution of rat intestinal metabolism to the xenobiotics clearance.

Michaelis-Menten constants K m and V max values were determined by product formation and substrate depletion at several substrate concentrations of 4-methylumbelliferone using rat intestinal microsomes. K m and V max values determined by measuring product formation were in good agreement with substrate depletion approach. We also investigated hepatic and intestinal in vitro intrinsic clearance (CLint) in the liver and intestinal microsomes and compare with reports in the literature using nine test compounds, atorvastatin, 7-ethoxycoumarin, indomethacin, 4-methylumbelliferone, midazolam, nifedipine, testosterone, terfenadine and verapamil, in rats. CLint was determined from the substrate disappearance rate at 0.1 and 0.5 µM in the rat intestinal and liver microsomes, respectively. These results showed that both the liver and the intestine contributed to the metabolism of these compounds. The intestinal intrinsic clearance values of all these drugs, except for terfenadine in the rat intestinal microsomes, were lower than their hepatic intrinsic clearance per milligram protein, showing that there was an organ difference in metabolism between the liver and intestinal. These results make the evaluation using the intestinal more useful and provide a basis for predicting clearance using intestinal.

[The development of secondary immunodeficiency in body when exposed to the effect of xenobiotics with immunosuppressive activity].

The State Education Institution of Higher professional education "The Orenburg State Medical Academy of Federal Agency in Public Health and Social Development". In the experiment on mice (CBA x C57Bl6) F1 and Wistar rats is shown the protective effect of triterpenoid plant--miliatsina (3-beta-methoxy-delta18-oleanena) in relation to the humoral immune response and clearance macrophage function hepatic xenobiotic conditions of use--methotrexate. The results define the term as used miliatsina immunoprotector with adverse effects on the body of environmental and industrial chemical factors that form the secondary immunodeficiency.

[Acute compartment syndrome in clinical toxicology]. / Ostry zespól ciasnoty przedzialów powieziowych w praktyce toksykologicznej.

In this article we described the basic information about diagnosis and treatment of acute compartment syndrome (acs). Rhabdomyolysis caused by standstill position, intramuscular injections of different xenobiotics, and hypo- and hyperthermia is the most common cause of acs among acute poisoned patients. The diagnosis may based on physical examination and direct measurement of tissue pressure. Treatment include prevention, and symptomatic therapy. In case of lack respond to symptomatic treatment the fasciotomy is needed.

Drug metabolism in the lungs: opportunities for optimising inhaled medicines.

INTRODUCTION: The lungs possess many xenobiotic metabolizing enzymes which influence the pharmacokinetics and safety of inhaled medicines. Anticipating metabolism in the lungs provides an opportunity to optimize new inhaled medicines and overcome challenges in their development. AREAS COVERED: This article summarizes current knowledge on xenobiotic metabolizing enzymes in the lungs. The impact of metabolism on inhaled medicines is considered with examples of how this impacts small molecules, biologics and macromolecular formulation excipients. Methods for measuring and predicting xenobiotic lung metabolism are critically reviewed and the potential for metabolism to influence inhalation toxicology is acknowledged. EXPERT OPINION: Drugs can be optimized by molecular modification to (i) reduce systemic exposure using a 'soft drug' approach, (ii) improve bioavailability by resisting metabolism, or (iii) use a prodrug approach to overcome pharmacokinetic limitations. Drugs that are very labile in the lungs may require a protective formulation. Some drug carriers being investigated for PK-modification rely on lung enzymes to trigger drug release or biodegrade. Lung enzyme activity varies with age, race, smoking status, diet, drug exposure and preexisting lung disease. New experimental technologies to study lung metabolism include tissue engineered models, improved analytical capability and in silico models.