药物基因组学-10-10-27课件.pptVIP

* * * * * * * Arg homozygotes had a 2-fold greater reduction in 24h DBP than Gly carriers. This was largely driven by differences in daytime DBP. Arg homozygotes had a 3-fold greater reduction in daytime DBP than Gly carriers * Figure 1. Example of the Response to Gefitinib in a Patient with Refractory Non-Small-Cell Lung Cancer. A computed tomographic scan of the chest in Patient 6 shows a large mass in the right lung before treatment with gefitinib was begun (Panel A) and marked improvement six weeks after gefitinib was initiated (Panel B). * * * * * * * * * * * * * * * * * * * * “That background understanding and the sequencing of the human genome have lead to the promise of Individualized Medicine (or PM)”—how much is hype or reality? * * * Here we have a schematic depiction of the factors related to the five determinants of drug activity. For the purposes of this presentation, we will be focusing on biotransformation systems in the Phase I or oxidative group of reactions. Within the Phase I group of reactions, we will deal specifically with the cytochrome P-450 or CYP superfamily of enzymes. * Metabolism can take place in many organs, but the liver frequently has the greatest metabolic capacity. The liver is the major site of drug metabolism. Most drugs undergo chemical modifications in the body so that they can eventually be eliminated. Very generally, these chemical reactions help to increase the water solubility of the drug so that it can be eliminated from the body, in most cases through the kidneys or the bile. Phase I: biotransformation reactions: oxidation, hydroxylation, reduction, hydrolysis—a polar functional group is added onto the substrate drug Phase II: conjugation reactions—add small molecules onto drugs to increase their water solubility and elimination from the body. The major reactions are glucuronidation, sulation, acetylation, glutathione conjugation * 是一组由结构和功能相关的超家族基因编码的含铁血红素同工酶 ，所有CYP450都含有一个非共价结合的血红蛋白 牢固地结合在细胞的内膜上，是一