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Grape pomace is the most important residual after wine making, and it is considered to be a very abundant source for the extraction of a wide range of polyphenols. These polyphenols exhibit a variety of bioactivities, such as antioxidant, anti-inflammatory, and anti-cancer. They are also beneficial in alleviating metabolic syndrome and regulating intestinal flora, etc. These health effects are most likely contributed by polyphenol metabolite, which are formed by the grape pomace phenolics after a complex metabolic process in vivo. Therefore, understanding the phenolic composition of grape pomace and its metabolism is the basis for an in-depth study of the biological activity of grape pomace polyphenols. In this paper, we first summarize the composition of phenolics in grape pomace, then review the recent studies on the metabolism of grape pomace phenolics, including changes in phenolics in the gastrointestinal tract, their pharmacokinetics in the systemic circulation, the tissue distribution of phenolic metabolites, and the beneficial effects of metabolites on intestinal health, and finally summarize the effects of human health status and dietary fiber on the metabolism of grape polyphenols. It is expected to provide help for the in-depth research on the metabolism and biological activity of grape pomace polyphenol extracts, and to provide theoretical support for the development and utilization of grape pomace. [ABSTRACT FROM AUTHOR]

For a new molecular entity (NME) to become a drug, it is not only essential to have the right biological activity also be safe and efficient, but it is also required to have a favorable pharmacokinetic profile including toxicity (ADMET). Consequently, there is a need to predict, during the early stages of development, the ADMET properties to increase the success rate of compounds reaching the lead optimization process. Since Lipinski's rule of five, the prediction of pharmacokinetic parameters has evolved towards the current in silico tools based on empirical approaches or molecular modeling. The commercial specialized software for performing such predictions, which is usually costly, is, in many cases, not among the possibilities for research laboratories in academia or at small biotech companies. Nevertheless, in recent years, many free online tools have become available, allowing, more or less accurately, for the prediction of the most relevant pharmacokinetic parameters. This paper studies 18 free web servers capable of predicting ADMET properties and analyzed their advantages and disadvantages, their model-based calculations, and their degree of accuracy by considering the experimental data reported for a set of 24 FDA-approved tyrosine kinase inhibitors (TKIs) as a model of a research project. [ABSTRACT FROM AUTHOR]

Lichens are among the most widely distributed plants on earth and have the longest growth cycle. Usnic acid is an abundant characteristic secondary metabolite of lichens and the earliest lichen compound used commercially. It has diverse pharmacological activities, such as anti-inflammatory, antibacterial, antiviral, anticancer, antioxidant, and photoprotective effects, and promotes wound healing. It is widely used in dietary supplements, daily chemical products (fodder, dyes, food, perfumery, and cosmetics), and medicine. However, some studies have found that usnic acid can cause allergic dermatitis and drug-induced liver injury. In this paper, the bioactivity, toxicity, in vivo and in vitro metabolism, and pharmacokinetics of usnic acid were summarized. The aims were to develop and utilize usnic acid and provide reference for its future research. [ABSTRACT FROM AUTHOR]

Immunosuppressive therapy is used in solid organ transplant treatment, and mycophenolic acid (MPA) is one of the immunosuppressive drugs most used worldwide. It is a potent, selective, non‐competitive, and reversible inosine monophosphate dehydrogenase (IMPDH) inhibitor that acts to inhibit guanine synthesis. To improve solubility, MPA is used as the prodrug mycophenolate mofetil (MMF) or as an enteric‐coated mycophenolate sodium salt (EC‐MPS). It is metabolized into mycophenolic acid phenyl glucuronide (MPAG), the inactive and major metabolite, and into acyl glucuronide (AcMPAG), pharmacologically active. In kidney transplantation, combined immunosuppressive therapy with cyclosporine (CsA) and tacrolimus (Tac) is widely used, showing beneficial effects. This paper aimed to review papers published in the last two decades and discuss factors that can interfere with the pharmacokinetics of MPA. Data collected confirm that MPA plasma levels should be monitored to evaluate immunosuppressive therapy since pharmacokinetics can be influenced by factors such as interpatient variability, coadministration of other immunosuppressive agents, post‐transplant period, renal function, and dose. However, to perform drug monitoring, costs and facility may be limitations. Monitoring MPAG together with MPA would be a great improvement in therapy as it represents a big part of MPA levels and can be related to the increase of adverse effects. [ABSTRACT FROM AUTHOR]

Many new chemical entities with tremendous therapeutic potential are discovered; yet, due to poor solubility and/or membrane penetration characteristics, many of these compounds have undesirable pharmacokinetic qualities. The latter is due to the lipid-like barrier imposed by epithelial mucosal layers, which drug molecules must cross to exert a therapeutic effect. Pre-systemic metabolic breakdown of drug compounds, primarily by cytochrome P450 enzymes found in intestinal enterocytes and liver hepatocytes, is another barrier. Although the nasal, buccal, and pulmonary modes of administration bypass the first-pass effect, systemic drug distribution is still reliant on drug molecules being absorbed via mucosal surfaces. Bio enhancers (naturally derived drug absorption enhancers) have been discovered to increase the amount of unaltered drug in the systemic blood circulation by regulating membrane permeability and/or pre-systemic metabolism. This paper attempts to give an overview of natural bio-enhancers and their key modes of action for medication administration via the nasal, buccal, pulmonary, and oral routes. Injections are frequently used to administer poorly bioavailable drugs, such as large, hydrophilic therapeutics. Bioenhancers may help patients by allowing for systemic distribution of these less bioavailable medications via alternative routes of administration (i.e., oral, nasal, buccal, or pulmonary routes of administration), as well as reducing dosages of tiny molecular pharmaceuticals and so lowering treatment costs. [ABSTRACT FROM AUTHOR]

Caenorhabditis elegans has emerged as a major model in biomedical and environmental toxicology. Numerous papers on toxicology and pharmacology in C. elegans have been published, and this species has now been adopted by investigators in academic toxicology, pharmacology, and drug discovery labs. C. elegans has also attracted the interest of governmental regulatory agencies charged with evaluating the safety of chemicals. However, a major, fundamental aspect of toxicological science remains underdeveloped in C. elegans: xenobiotic metabolism and transport processes that are critical to understanding toxicokinetics and toxicodynamics, and extrapolation to other species. The aim of this review was to initially briefly describe the history and trajectory of the use of C. elegans in toxicological and pharmacological studies. Subsequently, physical barriers to chemical uptake and the role of the worm microbiome in xenobiotic transformation were described. Then a review of what is and is not known regarding the classic Phase I, Phase II, and Phase III processes was performed. In addition, the following were discussed (1) regulation of xenobiotic metabolism; (2) review of published toxicokinetics for specific chemicals; and (3) genetic diversity of these processes in C. elegans. Finally, worm xenobiotic transport and metabolism was placed in an evolutionary context; key areas for future research highlighted; and implications for extrapolating C. elegans toxicity results to other species discussed. [ABSTRACT FROM AUTHOR]

The International Consortium for Innovation & Quality (IQ) in Pharmaceutical Development recently established a working group focused on the development of a guidance to address Deuterated Active Pharmaceutical Ingredients. Deuteration of an Active Pharmaceutical Ingredient (API) in some cases can retard and/or alter API metabolism by exploiting the primary kinetic isotope effect. Several deuterated APIs have entered into the clinic, and one has recently been approved. In most cases, it is very difficult to nearly impossible to synthesize a 100% isotopically pure compound. This raises synthetic, analytical, and regulatory questions that warrant a science‐based assessment and recommendations for synthetic methods, analytical methods, and specifications. A cross functional team of scientists with expertise in isotope chemistry, process chemistry, analytical chemistry, and drug metabolism and pharmacokinetics have been meeting under the auspices of IQ to define and address these questions. This paper strives to frame chemistry, manufacturing, and controls challenges. [ABSTRACT FROM AUTHOR]

The present paper deals with in silico evaluation of 32 virtually designed transition metal complexes of 2-butanone thiosemicarbazone and N,S,O containing donor hetero-ligands namely py, bpy, furan, thiophene, 2-picoline, 1,10-phenanthroline, piperazine and liquid ammonia. The complexes were designed with a view to assess their potential anticancer, antioxidant and antibacterial activity. The absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of the chosen ligands were calculated by admetSAR software. Metabolic sites of different ligands likely to undergo metabolism were predicted using Metaprint 2D. The proposed complexes were also evaluated for their drug-like quality based on Lipinski’s, Veber, Ghose and leadlikeness filters. Druglikeness and toxicity potential were predicted by OSIRIS property explorer. The pharmacokinetic properties and bioactivity scores were calculated by Molinspiration tool. Bioactivity scores of the complexes were predicted for drug targets including enzymes, nuclear receptors, kinase inhibitors, G-protein coupled receptor ligands and ion channel modulators. Molecular docking of selected Fe(II) mixed-ligand complexes was performed using AutoDock version 4.2.6 and i-GEMDOCK version 2.1 with two target proteins namely Ribonucleotide reductase (RR) and Topoisomerase II (Topo II). The results were compared with three standard reference drugs viz . Doxorubicin HCl, Letrozole (anticancer) and Tetracycline (antibiotic). Multivariate data obtained were analyzed using principal component analysis (PCA) for visualization and projection as scatter and 3D plots. Positive results obtained for hetero-ligands using admetSAR version 1.0 indicated good absorption and transport kinetics of the hetero-ligand complexes through the human intestine and blood-brain barrier. The hetero-ligands were predicted to have no associated mutagenic effect(s) also. However, none of the hetero-ligands was predicted to be Caco-2 (human colon cancer cell line) permeable. Most of the hetero-ligands and the parent ligand (2-butanone thiosemicarbazone) were predicted to undergo Phase-I metabolism prior to excretion using MetaPrint2D software. Pharmacokinetic evaluation of the proposed complexes revealed that all complexes displayed drug-like character and were predicted to have no apparent toxic side-effects. All the proposed complexes showed moderate to good biological activity scores (−5.0 to 0.0). Mixed complexes with bpy, 2-picoline and 1,10-phenanthroline showed significant bioactivity scores (as enzyme inhibitors) in the range 0.02–0.13. Likewise, good docking scores were obtained for Fe (II) complexes with the same ligands. [FeL(2-pic) 2 ] displayed the lowest binding energy (−6.47 kcal/mol) with respect to Topo II followed by [FeL(py) 2 ] (−6.14 kcal/mol) as calculated by AutoDock version 4.2.6. With respect to binding with RR, [FeL(2--pic) 2 ] again displayed the lowest binding energy (−7.21 kcal/mol) followed by [FeL(py) 2 ] (−5.96 kcal/mol). On the basis of docking predictions and various other computational evaluations, four mixed-ligand complexes of Fe in +2 oxidation state with py, bpy, 2--picoline and 1,10-phenanthroline were synthesized with 2-butanone thiosemicarbazone. All the synthesized Fe complexes were characterized using various spectroscopic techniques and tested for their potential anticancer activity in vitro against human breast carcinoma cell line MDA-MB 231 and human lung carcinoma cell line A549 cell line using MTT assay. [FeL(2-pic) 2 ], [FeL(bpy)], and [FeL(py) 2 ] were found to exhibit significant antiproliferative activity with IC 50 values in the range of 80–100 μM against breast and lung cancer cells. The synthesized Fe complexes also displayed mild antioxidant activities. The synthesized and studied Fe complexes have the potential for development into future anticancer agents if analyzed and modified further for improvement of their ADMET, solubility and permeability criteria set for potential drug-candidates. [ABSTRACT FROM AUTHOR]

Bisphenol S (BPS) has been introduced as a substitute for bisphenol A (BPA), and widely used in the manufacture of polycarbonate plastics, epoxy resins and thermal papers. Despite its adverse health outcomes and widespread exposure, pharmacokinetic data of BPS are not available for either animals or humans. The objective of the study is to describe pharmacokinetic characteristics of BPS in human body after a single oral administration with a compartmental pharmacokinetic model. Seven healthy young adults were orally exposed to 8.75 μg/bw of d 4 -BPS, and serum and urine samples were collected for 48 h. The concentrations of total and unconjugated d 4 -BPS in samples were measured using HPLC-MS/MS. Based on the time-concentration profiles in serum and urine, non-compartmental analysis was performed, and two-compartment model was constructed and validated. As a result of non-compartmental analysis, total d 4 -BPS was rapidly absorbed within 1 h (0.7 ± 0.3 h) after oral administration, and excreted in urine with terminal half-life of < 7 h (6.8 ± 0.7 h). Fractional urinary excretion (F ue ) of total d 4 -BPS for 48 h was 92 ± 17% (67–104%) for men and 70 ± 36% (59–77%) for women. The two-compartment model well described pharmacokinetic properties of BPS, and its parameter estimates were consistent with those from non-compartmental analysis. This study provides information on absorption, distribution, metabolism and elimination of BPS in human body, and the pharmacokinetic model can be utilized for estimating exposure dose of BPS, contributing to more realistic exposure assessment. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a multi-factor disease, in which metabolic disturbances played important roles. In this paper, functional information was integrated into a COPD-related metabolic network to assess similarity between genes. Then a gene prioritization method was applied to the COPD-related metabolic network to prioritize COPD candidate genes. The gene prioritization method was superior to ToppGene and ToppNet in both literature validation and functional enrichment analysis. Top-ranked genes prioritized from the metabolic perspective with functional information could promote the better understanding about the molecular mechanism of this disease. Top 100 genes might be potential markers for diagnostic and effective therapies. [ABSTRACT FROM AUTHOR]

The pharmacokinetic profile of a number of drugs has been shown to vary as a function of the time of day in the administration and thus apparently be under the influence of circadian rhythms: antiasthmatic, anticancer and cardiovascular products are but a few examples. Circadian rhythms may have influence on each of the processes of absorption, distribution, metabolism and elimination (ADME). Variations in pharmacokinetic quantities such as the Area under the curve (AUC), Mean Residence Time (MRT), time to the peak of concentration (t[sub max]) and value of the peak of concentration (C[sub max]) may therefore be expected. In this paper, we focus on possible variations in the peak of concentration C[sub max]. In contrast to a one-compartment model for time-varying pharmacokinetic quantities which has been shown [6] to display no variations in this quantity, we present a bi-compartmental model for time-varying systems to account for rapid intravenous dose, oral dose and intravenous infusion (zero order input). The effects of circadian rhythms on the maximal concentration of the drug in the body are studied for both single dose and multiple dosing, showing significant changes in values, induced by the time-varying coefficients in the PK model. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Portulaca oleracea L. is a widespread medicinal plant that is used not only as an edible plant, but also as a traditional medicine for alleviating a wide spectrum of diseases. It is a well-known plant in the European Traditional Medicine. PA is mentioned by Dioscorides (40–90 CE), with the name of “andrachne”. Aim of the review In this study, we provide detailed information on botany, traditional uses, phytochemistry, pharmacological uses, pharmacokinetics and safety of P. oleracea . Materials and methods An extensive search on electronic databases including PubMed, Web of Science, Google Scholar, ScienceDirect, Scopus, conference papers, local herbal encyclopedias, articles, books (in English, French, Arabic, Persian, etc .) and also a number of unpublished handwritten manuscripts was done to find articles have been published between 1956 and 2015 on pharmacology and phytochemistry of P. oleracea. Results P. oleracea has been addressed in De Materia Medica as an astringent, and a remedy for headaches, inflammation of the eyes and other organs, burning of the stomach, erysipela, disorders of the bladder, numbness of the teeth, excessive sexual desire, burning fevers, worms, dysentery, hemorrhoids, eruptions of blood, and bites. Phytochemical investigations revealed that this plant a wide range of secondary metabolites including alkaloids, terpenoids, flavonoids and organic acids. The most important pharmacological activities are renoprotective activities and effects on metabolism. P. oleracea could successfully decrease blood glucose and lipid profile of patients with metabolic syndrome. The safety of P. oleracea has been reported in many clinical trials. Conclusion Modern pharmacological studies have now proven many traditional uses of P. oleracea , including anti-hyperglycemic and anti-hyperlipidemic, renoprotective and hepatoprotective effects. In addition, in many clinical trials P. oleracea showed no adverse effects and constipation was reported as the most frequent adverse effect. [ABSTRACT FROM AUTHOR]

Identifying drug-drug interaction (DDI) is an important topic for the development of safe pharmaceutical drugs and for the optimization of multidrug regimens for complex diseases such as cancer and HIV. There have been about 150,000 publications on DDIs in PubMed, which is a great resource for DDI studies. In this paper, we introduced an automatic computational method for the systematic analysis of the mechanism of DDIs using MeSH (Medical Subject Headings) terms from PubMed literature. MeSH term is a controlled vocabulary thesaurus developed by the National Library of Medicine for indexing and annotating articles. Our method can effectively identify DDI-relevant MeSH terms such as drugs, proteins and phenomena with high accuracy. The connections among these MeSH terms were investigated by using co-occurrence heatmaps and social network analysis. Our approach can be used to visualize relationships of DDI terms, which has the potential to help users better understand DDIs. As the volume of PubMed records increases, our method for automatic analysis of DDIs from the PubMed database will become more accurate. [ABSTRACT FROM AUTHOR]

Human radiolabeled mass balance studies are performed to obtain information about the absorption, distribution, metabolism, and excretion of a drug in development. The main goals are to determine the route of elimination and major metabolic pathways. This review provides an overview of the current regulatory guidelines concerning human radiolabeled mass balance studies and discusses scientific trends seen in the last decade with a focus on mass balance studies of anticancer drugs. This paper also provides an overview of mass balance studies of anticancer agents that were executed in the last 10 years. [ABSTRACT FROM AUTHOR]

The aim of this paper was to analyze the impact of anesthesia induced by urethane on pharmacokinetics ( PK) parameters of fluconazole ( FCZ), mostly eliminated via renal excretion and voriconazole ( VRC), eliminated mainly by hepatic metabolism. FCZ and VRC PK were investigated after administration of 10 mg/kg i.v. and 5 mg/kg i.v. doses to awake and urethane anesthetized Wistar rats ( n = 6 per group), respectively. After dosing, blood samples were collected up to 18 h ( FCZ) or 12 h ( VRC) and the plasma data analysis was performed using the software MONOLIX v. 4.2.2. The population PK parameters and microconstants were determined by fitting plasma concentration-time profiles to two-compartment model for FCZ and three-compartment model for VRC. Fitting of FCZ plasma profiles after dosing to awake and anaesthetized animals resulted in a volume of distribution ( V) of 9.3 and 8.1 L/kg, and k10 values of 0.12 and 0.14 h−1, respectively. VRC plasma profiles in awake and anaesthetized showed V 8.7 of and 7.6 L/kg, and k10 of 0.15 and 0.16 h−1, respectively. No statistical differences between plasma PK parameters and microconstants for the same drug in both animal conditions studied were observed ( α = 0.05). © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3314-3318, 2015 [ABSTRACT FROM AUTHOR]

This comment is intended to discuss errors observed in the title paper, doi:10.3390/pharmaceutics12020134. When this paper was published, the authors of this commentary were excited to read it. However, the more we read, the more pitfalls were observed, which necessitated a response to revise the many errors and misleading information included in this publication. [ABSTRACT FROM AUTHOR]

Through pharmacological activity research, an increasing number of natural products and their derivatives are being recognized for their therapeutic value. In recent years, studies have been conducted on Corydalis yanhusuo W.T. Wang, a valuable medicinal herb listed in the Chinese Pharmacopoeia. Protopine, one of its components, has also become a research hotspot. To illustrate the identification, metabolism, and broad pharmacological activity of protopine and the botanical preparations containing it for further scientific studies and clinical applications, an in-depth and detailed review of protopine is required. We collected data on the identification and quantification, metabolism and pharmacokinetics, pharmacological activities, and botanical preparations of protopine from 1986 to 2021 from the PubMed database using "protopine" as a keyword. It has been shown that protopine as an active ingredient of many botanical preparations can be rapidly screened and quantified by a large number of methods (such as the LC-ESI-MS/MS and the TLC/GC-MS), and the possible metabolic pathways of protopine in vivo have been proposed. In addition, protopine possesses a wide range of pharmacological activities such as anti-inflammatory, anti-platelet aggregation, anti-cancer, analgesic, vasodilatory, anticholinesterase, anti-addictive, anticonvulsant, antipathogenic, antioxidant, hepatoprotective, neuroprotective, and cytotoxic and anti-proliferative activities. In this paper, the identification and quantification, metabolism and pharmacokinetics, pharmacological activities, and botanical preparations of protopine are reviewed in detail to lay a foundation for further scientific research and clinical applications of protopine. [ABSTRACT FROM AUTHOR]

Abstract: This paper aims to investigate the metabolism and pharmacokinetics of curcumin, demethoxycurcumin and bisdemethoxycurcumin in mice tumor. To improve water solubility, nanoparticle formulations were prepared as curcuminoids-loaded solid lipid nanoparticles (curcuminoids-SLNs) and curcumin-loaded solid lipid nanoparticles (curcumin-SLNs). After intragastric administration to tumor-bearing ICR mice, the plasma and tumor samples were analyzed by liquid chromatography with ion trap mass spectrometry. We discovered that curcuminoids were mainly present as glucuronides in plasma, whereas in free form in tumor tissue. A validated LC/MS/MS method was established to determine the three free curcuminoids in tumor homogenate. Samples were separated on a Zorbax SB-C18 column, eluted with acetonitrile–water (containing 0.1% formic acid), and detected by TSQ Quantum triple quadrupole mass spectrometer in selected reaction monitoring mode. The method showed good linearity (r 2 =0.997–0.999) over wide dynamic ranges (2–6000ng/mL). Variations within- and between-batch never exceeded 11.2% and 13.4%, respectively. The extraction recovery rates ranged from 78.3% to 87.7%. The pharmacokinetics of curcuminoids in mice tumor fit two-compartment model and first order elimination. For curcumin-SLNs group, the dosing of 250mg/kg of curcumin resulted in AUC(0–48h) of 2285ngh/mL and C max of 209ng/mL. For curcuminoids-SLNs group, the dosing equivalent to 138mg/kg of curcumin resulted in higher tumor concentrations (AUC=2811ngh/mL, C max =285ng/mL). It appeared that co-existing curcuminoids improved the bioavailability of curcumin. [Copyright &y& Elsevier]

Abstract: Curcumin and tetrahydrocurcumin (THC) have been found as potent DNMT1 inhibitors, but they suffer from low oral bioavailability and rapid metabolism in vivo. To circumvent these problems, two curcumin analogs: 1,7-bis(3,4-dimethoxyphenyl)-4,4-dimethyl-1,6-heptadiene-3,5-dione (TMC) and 1,7-bis(3,4-dimethoxyphenyl)-4-cyclohexyl-1,6-heptadiene-3,5-dione (DMCHC) have been synthesized to enhance their stability by blocking the two metabolic sites, the phenolic and C4 methylene moieties. Both compounds have shown inhibitory activity on M. SssI similar to that of curcumin and THC (Poster, M1114, AAPS, 2009). Preclinical pharmacokinetics has yet to be performed. In this paper, a simple liquid chromatography–tandem mass spectrometric method was developed for the determination of these four curcuminoids in cell medium and mouse plasma. The method showed linearity from 1 to 1000ng/mL with the lower limit of quantification of 1ng/mL in cell medium, and 5ng/mL in mouse plasma for all test curcuminoids. The within-day coefficients of variation were found to be below 15% and the accuracy was in the range of 85–115%. This method was subsequently used to evaluate their stability in these matrices and a pilot pharmacokinetics of curcumin, DMCHC and TMC in mice after an intraperitoneal (i.p.) cassette dosing of 10mg/kg each. Curcuminoids degraded in two phases with terminal half lives of 186, 813, 724, and 2000min for curcumin, THC, TMC, and DMCHC, respectively, in cell culture medium. In plasma, their respective half lives were 111, 232, 1202 and 3000min. These data demonstrated that their stability is in the order curcumin

The in vitro metabolism of two novel phosphate prodrugs of glycyrrhetic acid (GA) was studied by the method of incubation in the rat liver microsome and the in vivo plasma pharmacokinetics after injecting intravenously (i.v.) into six rats was investigated, respectively. The prodrugs diminished gradually with time and most of the parent drugs were released in 30 min in vitro. In this paper, the in vivo plasma concentration data were analyzed by compartmental modeling. Both the prodrugs and the corresponding released parent drugs could be described by a two-compartment model, which existed for 48 h in rats. The t1/2 increases remarkably after i.v. administration to rats when compared with injecting the parent drugs directly. [ABSTRACT FROM AUTHOR]

Absorption is a critical component of the pharmacokinetics for solid dosage forms administered orally. Many barriers must be overcome in order for a drug molecule to reach its effect site. To effectively address each of these barriers, drug-specific properties, formulation issues, and (patho)physiological changes in the gastrointestinal tract must be considered. First-pass metabolism in the gut and/or liver can dictate the extent to which a drug reaches the systemic circulation. Drug-metabolizing enzymes in the gut and liver are very susceptible to inhibition by other drugs, increasing the risk of drug interactions. In this paper, we will discuss absorption-related issues for solid dosage forms used in the management of stroke patients. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone. • Nicotine is a useful probe for phenotyping cytochrome P450 2A6 activity and chlorzoxazone is a frequently used probe for CYP2E1 activity. • The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities are unknown. WHAT THIS PAPER ADDS • This study demonstrates that CYP2A6 and CYP2E1 activities are not affected by nicotine dosing. • High-dose nicotine treatment has a low potential of interaction with CYP2A6 and CYP2E1 substrates. • The mechanisms of tobacco smoke-elicited changes in CYP2A6 and CYP2E1 activities are yet to be determined. AIMS Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone, which are probe reactions for cytochrome P450 2A6 (CYP2A6) and CYP2E1 activities, respectively. We aimed to determine the role of nicotine in these metabolic effects of cigarette smoking. METHODS The study had a single-blind, randomized, crossover two-arm design. Twelve healthy smokers were given two transdermal patches with 42-mg nicotine a day or placebo patches, each for 10 days. The subjects abstained from smoking during the study arms. Oral chlorzoxazone was given on day 7 and deuterium-labelled nicotine-d2 and cotinine-d4 infusion on day 8. RESULTS There was no significant influence of transdermal nicotine administration on pharmacokinetic parameters of nicotine-d2 or on the formation of cotinine-d2. Nicotine decreased the volume of distribution (62.6 vs. 67.7 l, 95% confidence interval of the difference −9.7, −0.6, P= 0.047) of infused cotinine-d4. There were no significant differences in disposition kinetics of chlorzoxazone between the treatments. CONCLUSIONS CYP2A6 and CYP2E1 activities are not affected by nicotine. The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities remain unknown. [ABSTRACT FROM AUTHOR]

The route followed by drug after its administration is known as LADME. Such route refers to liberation, absorption, distribution, metabolism and excretion. It is important to know each part of the process because it has a close relation with efficacy and toxicity of drugs. According with the route of administration used and the pharmaceutical presentation selected by the clinician, the drugs can reach and maintain their therapeutic purposes, which are defined by LADME. Minimal studies on LADME have been done in children, although recently they have increased. The purpose of this paper is to analyze the LADME route followed by drugs in children. [ABSTRACT FROM AUTHOR]

The drug development process is divided into phases with decisions required on compound selection and promotion to each subsequent development phase. In preclinical drug development the main objective is to bring the compound into human trials and there is an inability of many preclinical information packages to predict clinical responses. Since clinical responses are functions of the dose, the human dose anticipation should be a key deliverable of any preclinical package of drug candidate. The human dose should be anticipated by integration of information from multiple sources, in vitro and in vivo, non-human and human, using a variety of methodologies and approaches. Prediction of human safe and active dose relies on the availability of validated animal models for effect. Although there are many exceptions to the rule, the paper defines a four-step approach for the anticipation of human dose for first-in-man trials: 1, characterization of non-human exposure-response relationships; 2, correction for interspecies differences; 3, diagnosing compound absorption, distribution, metabolism and excretion (ADME) properties and prediction of human pharmacokinetics; and 4, prediction of human dose-responses and dose selection for phase I protocols. [ABSTRACT FROM AUTHOR]

Abstract: Posterior segment drug delivery challenges inherent in the treatment of many sight-threatening diseases have become increasingly apparent. Therapeutic interventions for ocular diseases such as neovascular retinopathies, inflammatory and/or infectious diseases may involve drug delivery to vitreoretinal targets. An important part of successful therapeutic strategies for such diseases involves verification that efficacious concentrations of the pharmacological agent are achieved within relevant intraocular regions. Microdialysis has been effectively employed for characterizing intraocular disposition in both anterior and posterior segments, providing important documentation of successful drug delivery to desired targets. Recent papers that showcase the maturation in the model development of microdialysis approaches for estimating posterior segment pharmacokinetics and further validation of the methodology are described in this review. Special problems examined include anterior and posterior ocular clearance mechanisms, intraocular metabolism and active transport of drugs. [Copyright &y& Elsevier]

Abstract: 2-hydroxylpropyl-β-cyclodextrin (HP-β-CD) is an alternative to α-, β- and γ-cyclodextrin, with improved water solubility and may be more toxicologically benign. This paper reviews the toxicity of HP-β-CD, using both literature information and novel data, and presents new information. In addition, it includes a brief review from studies of the metabolism and pharmacokinetics of HP-β-CD in both humans and animals. This review concludes that HP-β-CD is well tolerated in the animal species tested (rats, mice and dogs), particularly when dosed orally, and shows only limited toxicity. In short duration studies, there were slight biochemical changes whereas studies of a longer duration, up to three months, produced additional minor haematological changes but no histopathological changes. When dosed intravenously, histopathological changes were seen in the lungs, liver and kidney but all findings were reversible and no effect levels were achieved. The carcinogenicity studies showed an increase in tumours in rats in the pancreas and intestines which are both considered to be rat-specific. There were also non-carcinogenic changes noted in the urinary tract, but these changes were also reversible and did not impair renal function. There were no effects on embryo-foetal development in either rats or rabbits. HP-β-CD has been shown to be well tolerated in humans, with the main adverse event being diarrhoea and there have been no adverse events on kidney function, documented to date. [Copyright &y& Elsevier]

Whether children incur different risks from xenobiotics than adults will depend on the exposure, biokinetics, and dynamics of compound. In this paper, current knowledge on developmental physiology and possible effects on biokinetics are evaluated and the role of biokinetics in risk assessment both for drugs and chemicals is discussed. It is concluded that most dramatic age-related physiological changes that may affect biokinetics occur in the first 6–12 months of age. The difference in internal exposure between children and adults can generally be predicted from already known developmental physiological differences. However, for risk assessment it will also be necessary to determine whether internal exposure is within the drug’s therapeutic window or if it will exceed the NOAEL of a chemical. Furthermore, the effects of internal exposure of potentially harmful compounds on developing organ systems is of utmost importance. However, knowledge on this aspect is very limited. Risk assessment in children could be improved by: (1) application of pediatric PBPK-models in order to gain insight into internal exposure in children, (2) studies in juvenile animals for studying effects on developing systems, and (3) extrapolation of knowledge on the relationship between internal exposure and dynamics for drugs to other chemicals. [Copyright &y& Elsevier]

Absorption, distribution, metabolism and elimination are influenced by many different physiological functions of the body which may vary with time of day. Thus, the pharmacokinetic parameters characterising these different steps, conventionally considered to be constant in time, depend on the moment of drug administration. Time of day has to be regarded as an additional variable influencing the kinetics of a drug. Chronokinetic studies have been reported for many drugs in an attempt to explain chronopharmacodynamic phenomena and demonstrate that the time of administration is a possible factor of variation in the kinetics of a drug. In this paper this is illustrated with the chronopharmacokinetics of cardiovascular and nonsteroidal anti-inflammatory drugs. Time-dependent changes in kinetics may proceed from circadian variations at each step, e.g. absorption, distribution, metabolism and elimination. Thus, circadian variations in gastric acid secretion and pH, motility, gastric emptying time, gastrointestinal blood flow, drug protein binding, liver enzyme activity and/or hepatic blood flow, glomerular filtration, renal blood flow, urinary pH and tubular resorption may play a role in such kinetic variations. New tools, such as new formulation procedures or pumps with constant or programmable delivery rates, now make it possible to deliver a drug at a definite time, or during a definite span of time and at a controlled rate in chronokinetic studies. Microdialysis would be of particular interest in chronopharmacological and chronokinetics studies, but, surprisingly, very few chronobiological studies have been conducted using this technique. With regard to new models and concepts in chronokinetics, pharmacokinetic-pharmacodynamic modelling may be useful, and modelling of the chronopharmacological patterns of drug response and kinetics have been attempted by some authors. Drug chronopharmacokinetic knowledge may be clinically relevant as it may have implications for drug prescription by modulating the distribution of the total daily dose along the 24-hour scale. However, it seems reasonable to consider chronopharmacokinetic studies in specific cases related to patients, illness or the drug itself. When conducting a chronokinetic study it is not only necessary to take into account differences in the time of administration but to also have strict control of all other possible variables which are known to influence pharmacokinetic processes. [ABSTRACT FROM AUTHOR]

This paper reviews the current literature describing the metabolism of both multi-receptor clozapine analogue atypical antipsychotic drugs (clozapine, olanzapine, and quetiapine) and serotonin-dopamine antagonist atypical antipsychotic drugs (risperidone, sertindole and ziprasidone), to highlight the significance of those data in the context of clinical practice. The former group of atypical antipsychotic drugs shares a similar tricyclic structural nucleus and are metabolized through three major categorical metabolic pathways— N+-oxidation, N-glucuronidation, and phases 1 and 2 biotransformation with final glucuronidation before renal excretion. Differing in clozapine and olanzapine, quetiapine has incomplete data describing its metabolism. The latter group of atypical antipsychotic drugs has diversified chemical structures and absence of data on N+-oxidation and N-glucuronidation in the literature. But their metabolic routes in phase 1 biotransformation are versatile although current data are far from completion. No apparent significant drug interactions in clinical practice are reported, although QT prolongation is implicated in all those three drugs. None of all six atypical antipsychotic drugs are identified as significant inhibitors or inducers to any co-administered medication. The author suggests the need for more research to address some pertinent clinical issues in the metabolism of those drugs. [ABSTRACT FROM AUTHOR]

Many new chemical entities are discovered with high therapeutic potential, however, many of these compounds exhibit unfavorable pharmacokinetic properties due to poor solubility and/or poor membrane permeation characteristics. The latter is mainly due to the lipid-like barrier imposed by epithelial mucosal layers, which have to be crossed by drug molecules in order to exert a therapeutic effect. Another barrier is the pre-systemic metabolic degradation of drug molecules, mainly by cytochrome P450 enzymes located in the intestinal enterocytes and liver hepatocytes. Although the nasal, buccal and pulmonary routes of administration avoid the first-pass effect, they are still dependent on absorption of drug molecules across the mucosal surfaces to achieve systemic drug delivery. Bioenhancers (drug absorption enhancers of natural origin) have been identified that can increase the quantity of unchanged drug that appears in the systemic blood circulation by means of modulating membrane permeation and/or pre-systemic metabolism. The aim of this paper is to provide an overview of natural bioenhancers and their main mechanisms of action for the nasal, buccal, pulmonary and oral routes of drug administration. Poorly bioavailable drugs such as large, hydrophilic therapeutics are often administered by injections. Bioenhancers may potentially be used to benefit patients by making systemic delivery of these poorly bioavailable drugs possible via alternative routes of administration (i.e., oral, nasal, buccal or pulmonary routes of administration) and may also reduce dosages of small molecular drugs and thereby reduce treatment costs. [ABSTRACT FROM AUTHOR]

The article comments on the paper "Tissue-specific alterations in the 6-hydroxylation of chlorzoxazone following traumatic brain injury in the rat," by S.M. Poloyac and colleagues. According to the author, the study extends understanding of potential pharmacokinetic alterations after cardiac arrest, hypothermic conditions, and rewarming. He claims the blunting of hepatic drug metabolism by moderate hypothermia and normalization upon rewarming could have significant clinical implications.

Fulvestrant is a new type of oestrogen receptor (ER) antagonist with no agonist activity and a novel pharmacological profile. Fulvestrant has been shown to significantly reduce cellular levels of the ER and progesterone receptor in both preclinical studies and in clinical trials of postmenopausal women with primary breast cancer. This paper reviews the pharmacokinetics and metabolism of fulvestrant, which support the rationale for drug delivery as a single, once-monthly intramuscular injection, and show that this agent has minimal potential to be the subject, or cause, of significant cytochrome p450-mediated drug interactions.British Journal of Cancer (2004) 90(Suppl 1), S7-S10. doi:10.1038/sj.bjc.6601630 www.bjcancer.com [ABSTRACT FROM AUTHOR]