Interpretation of BDH for Drug Development

BDH can progress to cholangiocarcinoma with low margin of safety, a scenario that can lead to costly, late stage compound terminations and increased risk to patient safety. On the other hand, progression of BDH to neoplasia is not a certainty at least one blockbuster medication (Lipitor ) is taken chronically by patients to reduce cholesterol, in spite of the fact that this compound caused BDH at 3 months or less in both rats and dogs (NDA 20-702). Interpretation of the significance of BDH...

Radicals

Myeloperoxidase Adverse Drug Reactions

While radicals have been widely implicated in many toxicities, the chemical details of the mechanisms associated with these toxicities are less well defined. This is complicated in part by the fact that many radical forming drugs also generate electrophiles, and due to the difficulty in studying radicals in general. Radicals contain one or more unpaired electrons, and may participate in nucleophilc or electrophilic type reactions, but these are mechanistically distinct from the electrophilic...

Immunopathogenesis of Immune Mediated Idiosyncratic Drug Reactions

Pensamento

Our understanding of the pathogenesis of immune-mediated idiosyncratic reactions (IM-IDR) remains incomplete. There have been several recent reviews that address the possible mechanisms of IM-IDR and the reader is referred to these for detailed discussions (Park et al. 2001 Pirmohamed et al. 2002 Uetrecht 2003 Uetrecht 1999 Williams and Park 2003). Figure 1 presents the general paradigm that will be used to address the pathogenesis and prediction of idiosyncratic reactions. The initial...

Passive Diffusion

CNS Drugs Tend to be Basic (Clark, 2001) Scheme 10. CNS Drugs Tend to be Basic (Clark, 2001) Scheme 11 shows the correlation between in vivo brain permeability and H-bonds. Permeability decreased with increasing number of H-bonds for a series of steroids (Pardridge, 1995). BBB penetration also increases with increase in lipophilicity. Scheme 12 shows how replacement of one hydroxyl group of morphine with a methoxyl group to make codeine increased BBB penetration 10 fold. When both...

Aldehyde Compounds

Metabolic Activation-Role in Toxicity and Idiosyncratic Reactions Dept of Drug Metabolism Metabolic and Viral Center for Excellence in Drug Discovery GlaxoSmithKline Research Triangle Park North Carolina 27709 Types of Reactive Metabolites 52 Other Electrophilic Carbon Centers 62 Electrophiles Localized on Nitrogen or Sulfur, or Derived from Oxidation of Sulfur 65 P450 oxidase monooxygenase. Electrophile, Radical, Idiosyncratic reactions, Hepatotoxicity, Reactive metabolite, Acylators,...

If i

The influence of potential hydrogen bond acceptors as estimated by the number of O and N atoms on susceptibility of compounds to Pgp efflux. A compound is determined to be a Pgp substrate in this study if it has directional transport greater than 2 in transport studies with L-MDR1 cells. The number of compounds showing directional transport greater than 2 over the total number of compounds in each category is presented above the bar. toward false positive or false negative results....