Structure-pharmacokinetics relationship of quaternary ammonium compounds

Summary Correlations between lipophilicity or molecular weight and some pharmacokinetic parameters such as clearance (Cl), elimination rate constant (k ₁₀), volume of distribution (V), and terminal half life (_z) are presented for a series of structurally related quaternary ammonium cations (QACs). The structure-pharmacokinetics relations were fitted using the computer program NONLIN and were represented by linear, parabolic or S-shaped curves.The relationship between total plasma clearance or hepatic, renal and intestinal clearance and lipophilicity for the present set of data could be described most properly by the equation Y =1/(aX ^b), + c),where Y stands for the logarithm of the parmacokinetic parameters and X represents the logarithm of the values of some physicochemical parameters, such as the partition coefficient (P), the (HPLC) capacity factor k (another lipophilicity parameter) and molecular weight (MW). On the basis of this relationship, correlations of the hepatic or intestinal clearances with the lipophilicity parameters were good (r-0.98 and r=0.95 respectively). Curves relating values for partition coefficients and clearance via liver and intestine (expressed relative to the most simple QAC tetramethyl ammonium) showed S-shaped correlation patterns, in contrast to the renal clearance, which correlated poorly (r=0.54) with lipophilicity. The extent of biliary output of the organic cations shows a threshold phenomenon, sharply increasing at log P>1.5 to a maximum at P>2.5. This pattern was less pronounced in the case of intestinal elimination and absent in the case of renal clearance.The apparent maximum in the hepatic and intestinal clearance for the most lipophilic organic cations is probably due to limitation by organ blood-flow and/or plasma protein binding. After correction for these factors the resulting intrinsic clearance values indicate that membrane transport in the liver and intestine but not in the kidneys will tend to increase with the lipophilicity of the organic cation.     

Antimicrobial activity of quaternary ammonium compounds

The antimicrobial properties of two new imidazolium and pyridinium chlorides in comparison with three currently in disinfection compounds applied are described. The following research was performed: resistance of organisms to disinfectants and disinfection of hands. The new 3-methyl-n-dodecylthiomethylpyridinium chlorid was the most active compound.     

Airway effects of inhaled quaternary ammonium compounds in mice

Quaternary ammonium compounds (QAC) constitute a family of widely used chemical substances. The QAC benzalkonium chloride (BAC) has caused bronchoconstriction in human beings by poorly understood mechanisms and lung damage at high concentration as shown in a single rat study. This study evaluates acute airway effects in mice after inhalation of aerosols of the QACs, BAC, hexadecyl trimethyl ammonium bromide (HTA), cetyl pyridinium chloride (CPC) and dimethyl dioctadecyl ammonium bromide (DDA). The QACs gave rise to concentration-dependent decreases in the tidal volume (VT) and a concomitant increase in respiratory rate indicating pulmonary irritation. The potencies of the QAC to induce these effects were in the order: BAC > HTA = CPC > DDA. Furthermore, inhalation of BAC and CPC aerosols gave rise to pulmonary inflammation as apparent from bronchoalveolar lavage. Stimulation of nasal trigeminal nerve endings by QAC, which may serve as a warning signal, was absent.     

Virucidal activity of some quaternary ammonium compounds.

Four different quaternary ammonium compounds were tested by microtechniques for evaluating their activity against the type species of six viral groups very frequently involved in human and animal pathology. Three disinfectants showed good activity against five of the representative viruses under test, while the fourth proved less effective. Poliovirus type 1 was found to be completely resistant.     

The extraction and analysis of quaternary ammonium compounds in biological material by GC and GC/MS

An injection port pyrolysis method for the analysis of quaternary ammonium compounds is reported. Identification and confirmation of the analyte was accomplished by gas chromatography/mass spectrometry. With minor modifications to pH used and solvent composition, a common ion-pair method of extraction of quaternary ammonium compounds from biological matrices with an iodide counter ion is described. Although the combined extraction-identification methodology was limited to neostigmine, succinylcholine, and paraquat, it should easily be applicable to any of the other compounds examined in this study.     

Adjuvant effect of quaternary ammonium compounds in a murine model

It has been suggested that occupational exposure to quaternary ammonium compounds (QACs) may promote the development of allergic airway diseases. In this study, hazard identifications of the adjuvant effect of cetylpyridinium chloride (CPC), dimethyldioctadecylammonium bromide (DDA), hexadecyltrimethylammonium bromide (HTA), and tetraethylammonium chloride (TEA) were performed in a screening bioassay. Female BALB/c mice were injected subcutaneously with the model allergen ovalbumin (OVA) alone or together with different quantities of one of the QAC test compounds. After one or two boosters, levels of OVA-specific IgE, IgG1 and IgG2a antibodies were measured in sera. CPC and DDA increased IgE and IgG1 antibody production, respectively, compared to the OVA control group, whereas HTA and TEA showed no adjuvant effect. Nevertheless, when TEA was given in combination with DDA, the adjuvant effect was up to six-fold higher than the adjuvant effect of DDA alone. Only DDA had a statistically significant adjuvant effect on IgG2a antibody levels.     

生物样本中季铵类除草剂检测的研究进展

为精确检测生物样本中的百草枯、敌草快等季铵类除草剂提供参考,查阅国内外文献,对百草枯及敌草快的生物样本检测方法进行归纳和综述。结果显示,临床较为常用的检测方法为液相色谱法和液质联用法,受到检测方法、经济条件等因素影响。开展此类毒物检测的医院较少。生物样本中季铵类除草剂的检测方法仍需进一步的改进和推广,以更好地辅助临床诊断和治疗。     

Nitrosation of quaternary ammonium compounds in vivo in the Wistar rat

1. Animals dosed orally with nitrite (1.5 × 10^?3 mol/kg) and nonyl dimethylbenzylammonium bromide (2.9 × 10^?4 mol/kg) exhibit liver damage within two hours; cetyl trimethylammonium bromide plus nitrite was not significantly hepatotoxic.

2. Both nonyl dimethylbenzyl ammonium bromide and cetyl trimethylammonium bromide were demethylated by rat-liver microsomal preparations; substrate concentrations of 1 mM or more were inhibitory.

3. Bile from rats given i.p. doses of cetyl trimethylammonium bromide, nonyl dimethylbenzylammonium bromide or dodecyl dimethylbenzylammonium bromide contains only metabolites, no unchanged compounds were detected.     

Nitrosation of quaternary ammonium compounds in vivo in the Wistar rat

Animals dosed orally with nitrite (1.5 X 10(-3) mol/kg) and nonyl dimethylbenzylammonium bromide (2.9 X 10(-4) mol/kg) exhibit liver damage within two hours; cetyl trimethylammonium bromide plus nitrite was not significantly hepatotoxic. Both nonyl dimethylbenzyl ammonium bromide and cetyl trimethylammonium bromide were demethylated by rat-liver microsomal preparations; substrate concentrations of 1 mM or more were inhibitory. Bile from rats given i.p. doses of cetyl trimethylammonium bromide, nonyl dimethylbenzylammonium bromide or dodecyl dimethylbenzylammonium bromide contains only metabolites, no unchanged compounds were detected.     

A comprehensive screen for volatile organic compounds in biological fluids

A headspace gas chromatographic (GC) screen for common volatile organic compounds in biological fluids is reported. Common GC phases, DB-1 and DB-WAX, with split injection provide separation and identification of more than 40 compounds in a single 20-min run. In addition, this method easily accommodates quantitation. The screen detects commonly encountered volatile compounds at levels below 4 mg%. A control mixture, providing qualitative and semiquantitative information, is described. For comparison, elution of the volatiles on a specialty phase, DB-624, is reported. This method is an expansion and modification of a screen that had been used for more than 20 years. During its first year of use, the expanded screen has proven to be advantageous in routine forensic casework.     

Effects of quaternary ammonium compounds on choline transport in red cells

1. Neuromuscular blocking agents have been shown to be powerful inhibitors of choline transport in human erythrocytes. Ganglionic blocking agents were weaker inhibitors.2. The affinity of the choline transport site for alkyltrimethylammonium compounds was considerably higher than its affinity for alkyl-bis-(trimethylammonium) compounds of similar chain length. The affinity increases with increasing length of the alkyl chain in both series.3. Tetramethylammonium (TMA), ethyl- and propyltrimethylammonium appear to enter the cells on the choline carrier while the larger monoquaternary compounds, and the bisquaternary compounds, bind to the carrier but are unable to cross the cell membrane.4. Radioactively labelled carbachol, acetylcholine and decamethonium do not enter the cells on the choline carrier.5. Choline transport in erythrocytes from patients with myasthenia gravis is normal, suggesting that this disorder is not associated with a generalized defect of choline transport.