Organic anion-transporting polypeptides (OATPs) mediate the hepatic uptake of many drugs. Hepatic uptake is crucial for the therapeutic effect of pravastatin, a cholesterol-lowering drug and OATP1A/1B substrate. We aimed to gain empirical insight into the relationship between OATPs and pravastatin pharmacokinetics and toxicity. We therefore compared the distribution and toxicity of pravastatin in wild-type and Oatp1a/1b-null mice. Intestinal absorption of pravastatin was not affected by Oatp1a/1b absence, but systemic plasma exposure (AUC) increased up to 30-fold after oral bolus administration. This increased plasma exposure resulted from reduced hepatic uptake, as evident from 10 to 100-fold lower liver-to-plasma concentration ratios. However, the reductions in liver exposure were far smaller (<2-fold) than the increases in plasma exposure. Reduced pravastatin liver uptake in Oatp1a/1b-null mice was more obvious shortly after intravenous administration, with 8-fold lower biliary pravastatin excretion. A...
Dilek Iusuf; Rolf W. Sparidans; Anita van Esch; Mike Hobbs; Kathryn E. Kenworthy; Evita van de Steeg; Els Wagenaar; Jos H. Beijnen; Alfred H. Schinkel
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Scientists are reporting discovery of a potential biochemical basis for the apparent cancer-fighting ability of broccoli and its veggie cousins. They found for the first time that certain substances in the vegetables appear to target and block a defective gene associated with cancer. Their ... more
Scientists in Japan are reporting development of a faster, less expensive version of the fabled polymerase chain reaction (PCR) a DNA test widely used in criminal investigations, disease diagnosis, biological research and other applications. The new method could lead to expanded use of PCR ... more
Researchers at Rice University in Texas have developed a new approach to fighting cancer, based on nanoscale particles that can both detect and destroy cancerous cells. The report appears in the American Chemical Society's journal Nano Letters. Current molecular imaging approaches only dete ... more