Development of Human Membrane Transporters: Drug Disposition and Pharmacogenetics

Membrane transporters play an essential role in the transport of endogenous and exogenous compounds, and consequently they mediate the uptake, distribution, and excretion of many drugs. The clinical relevance of transporters in drug disposition and their effect in adults have been shown in drug–drug interaction and pharmacogenomic studies. Little is known, however, about the ontogeny of human membrane transporters and their roles in pediatric pharmacotherapy. As they are involved in the transport of endogenous substrates, growth and development may be important determinants of their expression and activity. This review presents an overview of our current knowledge on human membrane transporters in pediatric drug disposition and effect. Existing pharmacokinetic and pharmacogenetic data on membrane substrate drugs frequently used in children are presented and related, where possible, to existing ex vivo data, providing a basis for developmental patterns for individual human membrane transporters. As data for individual transporters are currently still scarce, there is a striking information gap regarding the role of human membrane transporters in drug therapy in children

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Canalicular microdomains and bile formation

This book is the proceedings of the XX International Bile Acid Meeting, Falk Symposium 165 entitled ‘Bile Acid Biology and Therapeutic Actions’, held in Amsterdam, The Netherlands, June 13--14, 2008, and dedicated to both basic and clinical aspects of bile acid research with a focus on the role of bile acids in hepatobiliary diseases. The latest findings are presented by leading scientists and clinicians in the field. Since the last International Bile Acid Meeting in Freiburg im Breisgau, Germany, in 2006, bile acid research has continued to flourish and therapeutic use of bile acids has attained a broader role. New insights have been gained into the mechanisms responsible for maintenance of bile acid homeostasis, and effects of bile acids on the cell signalling pathways have been further elucidated. Knowledge about the genetic basis of bile acid physiology has further increased. Therapy of chronic cholestatic liver diseases with ursodeoxycholic acid and new aspects of its chemopreventive properties continue to stimulate basic and clinical research and contribute to the understanding of underlying modes of action and to optimized treatment schedules

Effect of Nikel on Growth and Ultrastructure of Schizosaccaromyces Pombe

In this project, we investigated effects of nickel (Ni) on the growth and ultrastructure of Schizosaccharomyces pombe wild type strain. It was found that cells were tolerant against a concentration of 2 mM Ni+2 but the generation time was extended to 5 hours from 2.5 hours for the cells growing in Ni-free YEP medium. 76% of Ni+2 was removed in 30 min by the cells grown in YEP containing 1mM Ni+2. We also analyzed the ultrastructural modifications of the cells grown in 1 mM Ni+2. There was a visible thickening of the cell wall and increase in the number of small cytoplasmic vesicles. The plasma membrane appeared irregular compared to smoother contour in control. Vacuoles contained large amounts of electron-dense materials and the size of vacuoles also increased

Conjunctive Therapy of Cisplatin With the OCT2 Inhibitor Cimetidine: Influence on Antitumor Efficacy and Systemic Clearance

The organic cation transporter 2 (OCT2) regulates uptake of cisplatin in proximal tubules and inhibition of OCT2 protects against severe cisplatin-induced nephrotoxicity. However, it remains uncertain whether potent OCT2 inhibitors such as cimetidine can influence the antitumor properties and/or disposition of cisplatin. Using an array of preclinical assays, we found that cimetidine had no effect on the uptake and cytotoxicity of cisplatin in ovarian cancer cells with high OCT2 mRNA levels (IGROV-1). Moreover, the antitumor efficacy of cisplatin in mice bearing luciferase-tagged IGROV-1 xenografts was unaffected by cimetidine (P = 0.39). Data obtained in 18 patients receiving cisplatin (100 mg/m(2)) in a randomized crossover fashion with or without cimetidine (800 mg×2) revealed that cimetidine did not alter exposure to unbound cisplatin, a marker of antitumor efficacy (4.37 vs 4.38 μg×h/mL; P = 0.86). These results support the future clinical exploration of OCT2 inhibitors as specific modifiers of cisplatin-induced nephrotoxicity