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Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development.
This paper serves to provide one pragmatic approach to addressing the issue of bioactivation from an industry viewpoint based on protocols adopted by Merck Research Laboratories. Expand
The resurgence of covalent drugs
The prevalence and pharmacological advantages of covalent drugs are surveyed, how potential risks and challenges may be addressed through innovative design, and the broad opportunities provided by targeted covalENT inhibitors are presented. Expand
Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization.
The active forms of all marketed hydroxymethylglutaryl (HMG)-CoA reductase inhibitors share a common dihydroxy heptanoic or heptenoic acid side chain. In this study, we present evidence for theExpand
Mass spectrometry in the analysis of glutathione conjugates.
Mechanistic studies on metabolic interactions between gemfibrozil and statins.
A series of studies were conducted to explore the mechanism of the pharmacokinetic interaction between simvastatin (SV) and gemfibrozil (GFZ) reported recently in human subjects. After administrationExpand
Biotransformation of the naturally occurring isothiocyanate sulforaphane in the rat: identification of phase I metabolites and glutathione conjugates.
It is concluded that SFN undergoes metabolism by S-oxide reduction and dehydrogenation and that GSH conjugation is the major pathway by which the parent compound and its phase I metabolites are eliminated in the rat. Expand
Cytochrome P450 3A4-mediated bioactivation of raloxifene: irreversible enzyme inhibition and thiol adduct formation.
Data indicate that P450 3A4-mediated bioactivation of raloxifene in vitro is accompanied by loss of enzyme activity, which is effective in the treatment of osteoporosis in postmenopausal women. Expand
Is the role of the small intestine in first-pass metabolism overemphasized?
The primary function of the small intestine is to absorb nutrients and water. This is achieved by mixing food with digestive enzymes to increase the contact of foodstuffs with the absorptive cells ofExpand
Managing the challenge of chemically reactive metabolites in drug development
An assessment of the current approaches used for the evaluation of chemically reactive metabolites and how these approaches are being used within the pharmaceutical industry to assess and minimize the potential of drug candidates to cause toxicity is presented. Expand
Extrapolation of Diclofenac Clearance from in Vitro Microsomal Metabolism Data: Role of Acyl Glucuronidation and Sequential Oxidative Metabolism of the Acyl Glucuronide
Findings may have general implications in the use of total (free + conjugated) oxidative metabolite excretion for determining primary routes of drug clearance and may question the utility of diclofenac as a probe for phenotyping human CYP2C9 activity in vivo via measurement of its pharmacokinetics and total 4′-hydroxydicl ofenac urinary excretion. Expand