Release Of Aromatic Amines Research Articles

Metabolic Hydrolysis of Aromatic Amides in Selected Rat, Minipig, and Human In Vitro Systems

The release of aromatic amines from drugs and other xenobiotics resulting from the hydrolysis of metabolically labile amide bonds presents a safety risk through several mechanisms, including geno-, hepato- and nephrotoxicity. Whilst multiple in vitro systems used for studying metabolic stability display serine hydrolase activity, responsible for the hydrolysis of amide bonds, they vary in their efficiency and selectivity. Using a range of amide-containing probe compounds (0.5–10 µM), we have investigated the hydrolytic activity of several rat, minipig and human-derived in vitro systems - including Supersomes, microsomes, S9 fractions and hepatocytes - with respect to their previously observed human in vivo metabolism. In our hands, human carboxylesterase Supersomes and rat S9 fractions systems showed relatively poor prediction of human in vivo metabolism. Rat S9 fractions, which are commonly utilised in the Ames test to assess mutagenicity, may be limited in the detection of genotoxic metabolites from aromatic amides due to their poor concordance with human in vivo amide hydrolysis. In this study, human liver microsomes and minipig subcellular fractions provided more representative models of human in vivo hydrolytic metabolism of the aromatic amide compounds tested.

ChemInform Abstract: Reversible Capture and Release of Aromatic Amines by Vicinal Tricarbonyl Compound.

Abstract In this paper, we report reversible capture and release of aromatic amines by diphenylpropanetrione (DPPT). Addition of aromatic amines to the central carbonyl group occurred readily at ambient temperature to provide the aromatic amine adducts of DPPT (DPPT–aromatic amines), which has a hemiaminal structure. On the other hand, washing a solution of DPPT–aromatic amine with diluted hydrochloric acid (HCl) enabled successful recovery of DPPT to demonstrate the reversible nature of this system.

Reversible capture and release of aromatic amines by vicinal tricarbonyl compound

In this paper, we report reversible capture and release of aromatic amines by diphenylpropanetrione (DPPT). Addition of aromatic amines to the central carbonyl group occurred readily at ambient temperature to provide the aromatic amine adducts of DPPT (DPPT–aromatic amines), which has a hemiaminal structure. On the other hand, washing a solution of DPPT–aromatic amine with diluted hydrochloric acid (HCl) enabled successful recovery of DPPT to demonstrate the reversible nature of this system.

Influence of cationic polyelectrolytes on the kinetics and equilibria in pentacyanoiron(II) systems

The addition of a cationic polymer [poly(vinylbenzyltrimethylammonium), PVBA] increases the rate of release of aliphatic amines L from [Fe(CN)5L]3– by a factor that increases with increasing ratio R=[PVBA]/[Fe], and reaches a maximum of 2–3 at R= 8–10. For aromatic amine ligands, no rate enhancement is observed. The rate of the reverse formation reaction of [Fe(CN)5L](n–3) from [Fe(CN)5(H2O)]3– and Ln is affected only for n≠ 0, there being rate enhancement for anionic ligands and a rate decrease for cationic ligands. The influence on the rate of release of aliphatic amines is interpreted in terms of interactions between PVBA chains and the releasing ligand, whilst the rate changes in the reverse reaction are typical of the so-called ‘polyelectrolyte effect’ in bimolecular reactions. The dependence on PVBA molality of the rate of complex second-order reactions involving ion-pair formation as a pre-equilibrium is presented. By combining the effect on forward and reverse reaction, the influence of PVBA is shown to correspond to a linear free-energy relationship, with slope unity; this is in agreement with a mechanism involving dissociative activation. The lack of influence of PVBA on the rate of release of aromatic amines is probably due to compensating effects, as spectral changes suggest the possible operation of a parallel decrease in the rate constant. PVBA also affects the equilibrium between [Fe(CN)5NO]2– and [Fe(CN)5NO2]4– in alkaline media; the pK value is shifted by up to two units (for R= 12); further effects are observed related to the existence of other equilibria and/or slow irreversible processes that are also affected by the polycation.