V předložené studii se experimentálně stanovily dělící poměry diltiazemu v soustavě n-oktanolu a tlumivých roztoků o známém pH. Z těchto hodnot se vypočítaly rozdělovači koeficient a disociační konstanta diltiazemu. Léčivo s rozdělovacím koeficientem P = 597 a disociační konstantou Ka = 1,72 .10 (pKa = 7,76) bude mít předpoklady pro dobrou absorbci ve střevním traktu.
The present study experimentally determined the partition ratios of dilthiazem in the system of n-octanol and buffering solutions with known pH's. These values served to calculate the partition coefficient and dissociation constant of dilthiazem. The drug with the partition coefficient P = 597 and the dis association constant Ka = 1.72.10 (pKa=7.76) will have prerequisites for good absorption in the intestinal tract.
Medzi faktory, ktoré výrazne ovplyvňujú dostupnosť liečiva z liekovej formy, patria i pomocné látky, ktoré sú nevyhnutnou súčasťou pri formulácii lieku. Pri výbere pomocných látok pre novo formulovaný liek je potrebné vedieť, že liek nie je nikdy jednoduchou zmesou na sebe nezávislých zložiek, ale je to systém dynamický, v ktorom prebiehajú rôzne fyzikálne procesy i chemické pochody. Predložená práca je zameraná na štúdium vplyvu pomocných látok zo skupiny humektantov s odstupňovanou koncentráciou a konzervačnej prísady na rozdeľovací koeficient potenciálneho liečiva XIX M. Rozdeľovací koeficient (P’) bol stanovovaný v systéme n-oktanol/ vodný roztok s odstupňovanou koncentráciou polyolov. Pri týchto stanoveniach n-oktanol simuloval rohovú vrstvu, vodný roztok základ topického lieku. Z pomocných látok boli použité polyoly – glycerol, propylénglykol a sorbitol v 5; 10; 15 a 20% koncentrácii a antimikrobiálne účinný roztok Ajatinu® (Solutio benzododecinii bromati) v dvoch koncentráciach 0,01 a 0,1 % (m/m). Zo získaných výsledkov vyplýva, že na hodnoty rozdeľovacieho koeficientu potenciálneho liečiva XIX M majú veľký vplyv pomocné látky. Hodnota tohto parametra, a tým aj biologická dostupnosť, závisia nielen od druhu použitého polyolu a jeho koncentrácie, ale aj od koncentrácie použitej konzervačnej prísady, v tomto prípade Ajatinu®.
The factors which markedly influence availability of the drug from the dosage form include also auxiliary substances, which are an inevitable component in the formulation of the drug. In the selection of auxiliary substances for a newly formulated drug, it is necessary to know that the drug is never a simple mixture of mutually independent ingredients, but a dynamic system in which various physical and chemical processes take place. The present paper aims to study the effect of auxiliary substances from the group of humectants with graded concentrations and the effect of the preservative on the partition coefficient of potential drug XIX M. Partition coefficient (P’) was estimated in the system n-octanol/aqueous solution with graded concentrations of polyols. In these estimations, n-octanol simulated the horny layer, and the aqueous solution the base of the topical preparation. The auxiliary substances employed were polyols – glycerol, propylene glycol, and sorbitol in 5, 10, 15, and 20% concentrations and an antimicrobially effective solution of Ajatin® (Solution benzododecinii bromati) in two concentrations of 0.01 and 0.1 wt %. It follows from the obtained results that the values of partition coefficient of potential drug XIX M are greatly influenced by auxiliary substances. The value of this parameter, and therefore also biological availability, depend not only on the sort of the polyol used and its concentration, but also on the concentration of the preservative employed, in this case Ajatin®.
V práci sa sledoval vplyv pomocných, látok (propylénglykol, glycerol a sorbitol, ktoré ako humektanty a emolienty sú súčasťou niektorých základov topických prípravkov) na rozdeľovací koeficient (P') heptakaínu (XIX) a jeho morfollno- (XIX M), pyrolidíno- (XIX Z), 3-heptyloxy (XX Z), 2-pentyloxy(XIII) analógov a nesubstituovaného základného liečiva tejto série (IR-1). Obsah liečiv sa stanovoval v systéme n-oktanol/vodný roztok liečiva s prísadou 5; 10; 15 a 20% viacsýtnych alkoholov spektrofotometrický vo vodnej vrstve. Vplyv viacsýtnych alkoholov na P' sa nedá zovšeobecniť, pretože závisí od ich koncentrácie ako aj od druhu lokálneho anestetika, napr. F látky XIX M sa s rastúcou koncentráciou propylénglykolu znižuje a naopak s rastúcou koncentráciou sorbitolu zvyšuje. Z toho vyplýva, že k formulácii liekovej formy s uvedenými lokálnymi anestetikami treba pristupovať vždy individuálne.
The paper examined the effects of auxiliary substances (propyleneglycol, glycerol and sorbitol which as humestants and emollients are components of some bases of topical preparations) on the partition coefficient (P) of heptacaine (XIX) and its morpholino- (XIX M), pyrolidino- (XIX Z), 3-heptyloxy (XX Z), 3-pentyloxy- (XIII) analogues and the unsubstituted fundamental drug of this series (IR-1). The content of drugs was determined in the system n-octanol/aqueous solution of the drug with an addition of 5; 10; 15 and 20% of multisaturate alcohols spectrophotometrically in an aqueous layer. The effect of multisaturate alcohols on P caimot be generalized as it depends on their concentration as well as the sort of the local anaesthetic agent, e .g. P of substance XIXM is decreased with increasing concentration and, on the other hand, it is increased with increasing sorbitol concentration. The results show that formulation of a dosage form including these local anaesthetics must be always approached individually.
Over the past decade, molecular dynamics (MD) simulations have become particularly powerful to rationalize drug insertion and partitioning in lipid bilayers. MD simulations efficiently support experimental evidences, with a comprehensive understanding of molecular interactions driving insertion and crossing. Prediction of drug partitioning is discussed with respect to drug families (anesthetics; β-blockers; non-steroidal anti-inflammatory drugs; antioxidants; antiviral drugs; antimicrobial peptides). To accurately evaluate passive permeation coefficients turned out to be a complex theoretical challenge; however the recent methodological developments based on biased MD simulations are particularly promising. Particular attention is paid to membrane composition (e.g., presence of cholesterol), which influences drug partitioning and permeation. Recent studies concerning in silico models of membrane proteins involved in drug transport (influx and efflux) are also reported here. These studies have allowed gaining insight in drug efflux by, e.g., ABC transporters at an atomic resolution, explicitly accounting for the mandatory forces induced by the surrounded lipid bilayer. Large-scale conformational changes were thoroughly analyzed.
- MeSH
- Biological Transport MeSH
- Cell Membrane metabolism MeSH
- Cytoplasm metabolism MeSH
- Pharmaceutical Preparations metabolism MeSH
- Drug Resistance MeSH
- Humans MeSH
- Lipid Bilayers metabolism MeSH
- Membrane Proteins metabolism MeSH
- Computer Simulation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Phthalates are a class of compounds that have been extensively used as plasticizers in different applications. Several phthalates have been recognized as substances of very high concern (SVHCs) in the EU, because of their toxicity for reproduction. However, high amounts of other phthalates are still produced and imported in the European Economic Area. In China and the US, recent studies show increasing concentrations of several phthalates in the air and in human urine, respectively. The understanding of phthalate absorption, distribution, metabolism, and elimination ('pharmacokinetics') in the organism is still limited. Specifically, phthalate partitioning among tissues is insufficiently understood. Here, we estimate partition coefficient (PC) values for different phthalates by using five algorithms and compare them to experimental (in-vivo and in-vitro) PC values. In addition, we review all pharmacokinetic steps for phthalates in human and rat, based on data from 133 peer-reviewed publications. We analyze the factors that determine phthalate partitioning and pharmacokinetics. Four processes are particularly relevant to phthalate distribution: protein binding, ionization, passive partitioning, and metabolism in different tissues. The interplay of these processes needs to be better represented in methods for determining the PC values of phthalates. The hydrophobicity of phthalates affects all pharmacokinetic steps. The exposure route has an influence on specific steps of phthalate pharmacokinetics but generally does not affect the pattern of metabolites in urine. The age of the organism has an influence on phthalate metabolism. More studies on the protein-bound fraction of phthalates in plasma and pharmacokinetic studies following inhalation and dermal exposure are desirable.
- MeSH
- Rats MeSH
- Phthalic Acids chemistry pharmacokinetics MeSH
- Humans MeSH
- Tissue Distribution MeSH
- Plasticizers chemistry pharmacokinetics MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
The occurrence and atmospheric behavior of tri- to deca-polybrominated diphenyl ethers (PBDEs) were investigated during a 2-week campaign concurrently conducted in July 2012 at four background sites around the Aegean Sea. The study focused on the gas/particle (G/P) partitioning at three sites (Ag. Paraskevi/central Greece/suburban, Finokalia/southern Greece/remote coastal, and Urla/Turkey/rural coastal) and on the size distribution at two sites (Neochorouda/northern Greece/rural inland and Finokalia/southern Greece/remote coastal). The lowest mean total (G + P) concentrations of ∑7PBDE (BDE-28, BDE-47, BDE-66, BDE-99, BDE-100, BDE-153, BDE-154) and BDE-209 (0.81 and 0.95 pg m-3, respectively) were found at the remote site Finokalia. Partitioning coefficients, K P, were calculated, and their linear relationships with ambient temperature and the physicochemical properties of the analyzed PBDE congeners, i.e., the subcooled liquid pressure (P L°) and the octanol-air partition coefficient (K OA), were investigated. The equilibrium adsorption (P L°-based) and absorption (K OA-based) models, as well as a steady-state absorption model including an equilibrium and a non-equilibrium term, both being functions of log K OA, were used to predict the fraction Φ of PBDEs associated with the particle phase. The steady-state model proved to be superior to predict G/P partitioning of BDE-209. The distribution of particle-bound PBDEs across size fractions < 0.95, 0.95-1.5, 1.5-3.0, 3.0-7.2, and > 7.2 μm indicated a positive correlation between the mass median aerodynamic diameter and log P L° for the less brominated congeners, whereas a negative correlation was observed for the high brominated congeners. The potential source regions of PBDEs were acknowledged as a combination of long-range transport with short-distance sources.
- MeSH
- Adsorption MeSH
- Halogenated Diphenyl Ethers analysis MeSH
- Air Pollutants analysis MeSH
- Environmental Monitoring * MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Greece MeSH
The dissipation, partitioning dynamics and biouptake was measured for selected hazardous current-used pesticides (conazole fungicides: epoxiconazole, flusilazole, tebuconazole; prochloraz, chlorpyrifos, pendimethalin) and for a transformation product (2-hydroxyatrazine) in agricultural soil and quartz sand as representatives of a real and a worst-case scenario. Dissipation, uptake to Lactuca sativa and the freely dissolved concentration along with the organic carbon-normalized sorption coefficients (Koc) were determined on days 12, 40, and 90 following the application of compounds at three fortification levels (0.1-1.0-10 mg/kg). Conazole fungicides showed similar dissipation patterns and were more persistent in soil than prochloraz, chlorpyrifos and pendimethalin. 2-Hydroxyatrazine showed a concentration-depended decrease in persistency in soil. Lettuce roots were shown to accumulate higher amounts than shoots where the extent of root uptake was driven by compound partitioning. This was evidenced by the ability of freely dissolved concentration (Cfree) to reliably (r2 = 0.94) predict root uptake. Concentration in leaves did not exceed the maximum residue levels (MRLs) for lettuce, which was likely given by the low root-to-shoot translocation factors (TFs) of the tested compounds varying between 0.007 and 0.14. Koc values were in the range of literature values. Sorption to soil was higher than to sand for all compounds, yet following the Koc dynamics compounds did not appear to be sequestered in soil with increasing residence time. From these results, it follows that the tested compounds may persist in soil but since they did not accumulate in lettuce above MRLs, contamination of the food web is unlikely.
- MeSH
- Atrazine analogs & derivatives analysis pharmacokinetics MeSH
- Plant Roots metabolism MeSH
- Soil Pollutants analysis MeSH
- Plant Leaves metabolism MeSH
- Pesticides analysis pharmacokinetics MeSH
- Fungicides, Industrial analysis pharmacokinetics MeSH
- Lactuca metabolism MeSH
- Publication type
- Journal Article MeSH
