Current Drug Metabolism - Volume 12, Issue 3, 2011

The question to what extent acyl glucuronides, which are chemically reactive electrophiles formed from carboxylic acid-containing drugs, should be considered a potential hazard in drug development is an old bone of contention. On the one hand, a recent guideline issued by the FDA in 2008 states that “…if a conjugate forms a toxic compound such as acylglucuronide, additional safety assessment may be needed…” [1]. If on Read More

This review presents a survey of acyl glucuronides (AGs) from the perspective of a synthetic medicinal chemist. After a brief introduction to the biogenesis of AGs and current attitudes of the pharmaceutical industry towards them, the importance of the availability of pure synthetic AGs as probe molecules is stressed. Current synthetic methods including the selective acylation method and enzymatic procedures are discusse Read More

This review on isomers or acyl glucuronides (iso-glucuronides) updates earlier reviews, and attempts to place in context the advances that have been made, especially over the last 15 years. The essential chemistry behind the intramolecular acyl migration and anomerization reactions of acyl glucuronides has been appreciated for 30 years. The great advances in the past 15 years have been in understanding the dynamics and Read More

Carboxylic acid-containing drugs can be metabolized to chemically-reactive acyl glucuronide, S-acyl-CoA thioester, and/or intermediate acyl-adenylate metabolites that are capable of transacylating the cysteinyl-thiol of glutathione (GSH) resulting in the formation of drug-S-acyl-GSH thioesters detected in vivo in bile and in vitro in hepatocytes. Authentic S-acyl-GSH thioesters of carboxylic acids can be readily synthesiz Read More

Many nonsteroidal anti-inflammatory drugs (NSAIDs) are carboxylic acid-containing compounds that are conjugated in the liver to acyl glucuronides and excreted across the hepatocanalicular membrane into bile. Chronic and acute NSAID use has not only been associated with gastric injury but also increasingly recognized to cause small intestinal injury (enteropathy). The mechanisms of NSAID enteropathy are still unknown, but Read More

Mammalian Target Of Rapamycin (mTOR) inhibitors represent a new class of immunosuppressant drugs extensively used for the prevention and the treatment of graft rejection in organ transplant recipients. Their current use is due to referred low nephrotoxic effects, particularly important in kidney transplanted and/or patients with renal failure. The most representative drugs of such class are Sirolimus (Siro) and Everolimus ( Read More

Human multidrug resistance ABC transporters are ubiquitous membrane proteins responsible for the efflux of multiple, endogenous or exogenous, compounds out of the cells, and therefore they are involved in multi-drug resistance phenotype (MDR). They thus deeply impact the pharmacokinetic parameters and toxicity properties of drugs. A great pressure to develop inhibitors of these pumps is carried out, by eit Read More

It is well known that interindividual variability can affect the response to many drugs in relation to age, gender, diet, and organ function. Pharmacogenomic studies have also documented that genetic polymorphisms can exert clinically significant effects in terms of drug resistance, efficacy and toxicity by modifying the expression of critical gene products (drug-metabolizing enzymes, transporters, and target molecul Read More

Metallometabolomics is an emerging field integrating the research technologies related to the comprehensive analysis of metabolites of a metallodrug in a biologically relevant sample, requiring high-throughput and targeted analyses of the transformation, speciation, localization and structural characteristics of the metallometabolites. This review discusses the concept of metallometabolomics with a focus on analytica Read More

The xenobiotic response represents a complex group of chemical reactions aimed to inactivate and eliminate foreign chemicals, to antagonize their toxic effects, and to repair eventually damaged tissues. Intriguingly, xenobiotic response is also active against endogenous products of metabolism. Members of the nuclear receptor superfamily play a key role in xenobiotic detection and response. In particular, the constitutive androst Read More