Identification of alcohol-dependent clopidogrel metabolites using conventional liquid chromatography/triple quadrupole mass spectrometry.

Rationale: Clopidogrel (CLO) is a prodrug used to prevent ischemic events in patients undergoing percutaneous coronary intervention or with myocardial infarction. A previous study found ethyl clopidogrel (ECLO) is formed by transesterification of CLO when incubated with alcohol in human liver microsomes. We hypothesize that ECLO will be subject to further metabolism and developed an assay to identify its metabolites.

Identification of carboxylesterase-dependent dabigatran etexilate hydrolysis.

Dabigatran etexilate (DABE) is an oral prodrug that is rapidly converted to the active thrombin inhibitor, dabigatran (DAB), by serine esterases. The aims of the present study were to investigate the in vitro kinetics and pathway of DABE hydrolysis by human carboxylesterase enzymes, and the effect of alcohol on these transformations. The kinetics of DABE hydrolysis in two human recombinant carboxylesterase enzymes (CES1 and CES2) and in human intestinal microsomes and human liver S9 fractions were determined.

Nonvolatile salt-free stabilizer for the quantification of polar imipenem and cilastatin in human plasma using hydrophilic interaction chromatography/quadrupole mass spectrometry with contamination sensitive off-axis electrospray.

A hydrophilic interaction chromatography/mass spectrometry (HILIC-MS)-based assay for imipenem (IMP) and cilastatin (CIL) was recently reported. This orthogonal electrospray ion source-based (ORS) assay utilized nonvolatile salt (unremovable) to stabilize IMI in plasma. Unfortunately, this method was not applicable to conventional MS with off-axis spray (OAS-MS) because MS sensitivity was rapidly deteriorated by the nonvolatile salt.

The role of human carboxylesterases in drug metabolism: have we overlooked their importance?

Carboxylesterases are a multigene family of mammalian enzymes widely distributed throughout the body that catalyze the hydrolysis of esters, amides, thioesters, and carbamates. In humans, two carboxylesterases, hCE1 and hCE2, are important mediators of drug metabolism. Both are expressed in the liver, but hCE1 greatly exceeds hCE2.

Conventional liquid chromatography/triple quadrupole mass spectrometry based metabolite identification and semi-quantitative estimation approach in the investigation of in vitro dabigatran etexilate metabolism.

Dabigatran etexilate (DABE) is an oral prodrug that is rapidly converted by esterases to dabigatran (DAB), a direct inhibitor of thrombin. To elucidate the esterase-mediated metabolic pathway of DABE, a high-performance liquid chromatography/mass spectrometry based metabolite identification and semi-quantitative estimation approach was developed. To overcome the poor full-scan sensitivity of conventional triple quadrupole mass spectrometry, precursor-product ion pairs were predicted to search for the potential in vitro metabolites.

Simple and sensitive assay for quantification of oseltamivir and its active metabolite oseltamivir carboxylate in human plasma using high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry: improved applicability to pharmacokinetic study.

Although liquid chromatography/electrospray ionization tandem mass spectrometry-based assays have been reported for the measurement of the antiviral oseltamivir (OS) in human samples, these assays either involve complicated sample pretreatment or lack sensitivity. Here we introduce a straightforward approach to improve the assay performance for OS and its metabolite oseltamivir carboxylate (OSC) in human plasma. A very low concentration of mobile phase modifier can improve the ionization efficiency of both analytes, thus enabling a high sensitivity without any matrix effect.

Heat-induced superaggregation of amphotericin B attenuates its ability to induce cytokine and chemokine production in the human monocytic cell line THP-1.

The cytokine and chemokine response elicited by heat-treated amphotericin B (HT-AmB) was compared with that of untreated amphotericin B (AmB-DOC) in the human monocyte cell line THP-1. AmB-DOC produced dose-dependent increases in interleukin (IL)-1beta, IL-1alpha, tumour necrosis factor-alpha, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta at 2 h. HT-AmB induced cytokine and chemokine production at a lower level than those observed with corresponding concentrations of AmB-DOC, while retaining antifungal activity.

Aerosolized ceftazidime for prevention of ventilator-associated pneumonia and drug effects on the proinflammatory response in critically ill trauma patients.

Study Objectives: To evaluate the safety and efficacy of aerosolized ceftazidime for prevention of ventilator-associated pneumonia (VAP) and to evaluate the effects of the drug on the proinflammatory response.

Design: Prospective, randomized, double-blind, placebo-controlled clinical trial.

Setting: University teaching hospital.