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1.
《Drug metabolism and pharmacokinetics》2020,35(1):56-70
Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CLh) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CLh involving OATP1B-mediated hepatic uptake. CLh can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CLh and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction. 相似文献
2.
Interneurons immunoreactive for vasoactive intestinal polypeptide (VIP) are integral elements of columnar organization patterns in the rat cerebral cortex. By application of the sensitive mirror technique, the co-localization of VIP with the classical inhibitory neurotransmitter γ-aminobutyric acid (GABA) and the acetylcholine-synthesizing enzyme, choline acetyltransferase (ChAT), was investigated in neocortical neurons. Furthermore, the frequency of co-localization of ChAT with GABA was determined. In a sample of 118 VIP-immunoreactive neurons, mostly from the primary somatosensory cortex, it was demonstrated that virtually all of them reveal immunoreactivity for GABA and, therefore, are to be GABAergic. Moreover, 34% of mostly bipolar, VIP-positive neurons contained ChAT and are, thus, supposedly cholinergic as well. Co-localization of VIP and ChAT varied according to cortical laminae. Finally, 88% of a total of 60 ChAT-immunoreactive neurons were also immunostained for GABA. It is concluded that almost all VIP-immunoreactive neurons and most of the cholinergic neurons in rat neocortex represent partly overlapping subpopulations of inhibitory interneurons utilizing GABA. 相似文献
3.
PACAP is a hypothalamic hypophysiotropic factor that acts upon a number of pituitary cells, including gonadotrophs. In the gonadotroph-derived αT3-1 cell line, PACAP acts via PVR1 receptors to stimulate adenylyl cyclase and phosphoinositidase C. PACAP-stimulated cAMP accumulation is inhibited by protein kinase C-activating phorbol esters in these cells and the current work was undertaken primarily to establish whether it is also subject to homologous regulation. In acute experiments, PACAP27-stimulated cAMP accumulation (intracellular plus extracellular) was measured (in the presence of phosphodiesterase inhibitor) both in intact cells and in cell membranes. The peptide increased cAMP accumulation, but initial rates of PACAP27-stimulated cAMP accumulation were reduced to between 10 and 50% within 10 min of stimulation in both cells and membranes. The initial rate of forskolin-stimulated cAMP accumulation was maintained in membranes but not in intact cells (although the deviation from linearity was less pronounced than with PACAP27). Thus, rapid homologous desensitization to PACAP27 occurs in intact αT3-1 cells, but is not entirely receptor specific. Rapid homologous desensitization of PACAP27-stimulated cAMP accumulation also occurred in the presence of a protein kinase C activating phorbol ester, which inhibited cAMP accumulation without altering the kinetics of the PACAP27 effect. Brief pre-treatment (3 min) with PACAP27 also reduced the ability of PACAP27, but not gonadotrophin-releasing hormone, to cause a spike-type elevation of cytosolic Ca2+ concentration (a consequence of phosphoinositidase C activation). In chronic desensitization studies, pre-treatment for 6 h with PACAP27 caused a dose-dependent (IC50 approximately 10 nM) reduction of PACAP-stimulated cAMP accumulation and down regulated cell surface PVR1 receptors (to approximately 50%). Thus, it appears that PACAP27-stimulated (PVR-1 receptor mediated) adenylyl cyclase undergoes rapid homologous desensitization in αT3-1 cells, which is paralleled by homologous desensitization of PACAP27-stimulated phosphoinositidase C activity and involves mechanisms distinct from those underlying heterologous desensitization by phorbol esters. Chronic desensitization of PACAP-stimulated cAMP accumulation and down-regulation of cell surface PVR-1 receptors also occurs in these cells although the receptor loss may not entirely explain the observed desensitization. 相似文献
4.
目的:分离鉴定鹿茸中神经节苷脂的成分。方法:Folsh分配、DEAE-Cellulose柱层析分离、薄层色谱方法鉴定。结果:分离鉴定出3种组分(A、B、C),与对照品薄层图谱对照,鉴定了A为GM4,B为GM3,C为GD3,A、B、C的百分含量分别为24.4%、46.2%、29.4%。结论:首次从鹿茸中分离出GM4,GM3,GD33种神经节苷脂成分。 相似文献
5.
目的探讨经鹿茸多肽(PAP)诱导的兔自体骨髓间质干细胞(MSCs)复合胶原膜(MCMG)对兔膝关节局部全层软骨缺损的修复作用。方法新西兰大白兔随机分成A,B,C3组,A组以PAP诱导后的自体MSCs和MCMG修复软骨缺损;B组以经转化生长因子β1(TGF-β1)诱导后的自体MSCs和MCMG修复软骨缺损;C组以自体MSCs和MCMG修复软骨缺损。分别于术后2、4和8周取材进行大体、组织学及免疫组织化学染色观察,根据关节软骨组织学计分标准进行评分。结果对术后8周大体及各阶段组织学形态评分结果显示:A组与B组修复差别无统计学意义(P>0.05),而A、B组明显优于C组(P<0.05)。结论经PAP诱导的兔自体MSCs/MCMG支架复合物可促进软骨缺损的快速修复,恢复软骨组织的结构和功能。 相似文献
6.
蝎毒多肽提取物对肺癌荷瘤裸鼠血流变学的影响 总被引:2,自引:0,他引:2
目的观察蝎毒多肽提取物(PESV)对肺癌荷瘤裸鼠血流变学的影响。方法移植肺癌荷瘤裸鼠随机分为PESV组(皮下注射PESV)与对照组(皮下注射生理盐水)。采用FASCO-300型全自动表观黏度快测仪对两组的全血黏度进行检测。结果与对照组相比,PESV组血流变学指标均有不同程度的降低,尤其是全血低切表观黏度、全血高切表观黏度、Casson黏度、Casson屈服应力均明显低于对照组(P〈0.01)。结论PESV可降低荷瘤裸鼠血液黏度,对肺癌荷瘤裸鼠肿瘤转移能力有明显的抑制作用。 相似文献
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9.
血清TPS浓度在消化道肿瘤中价值的研究 总被引:4,自引:0,他引:4
共选择30例消化道肿瘤病人,其中食管癌,胃癌,大肠癌各10例,设健康献血者30例,对两组血清特异型组织多肽抗原浓度进行了检测,结果肿瘤组血清TPS浓度明显高于健康人。消化道肿瘤阳性检出经达70%,其中食管癌80%,胃癌60%,大肠癌70%。消化道肿瘤合并淋巴转移阳性检出率达76.9%,其中食管癌100%,胃癌66.7%,大肠癌70.0%。随着病程发展,血清TPS浓度呈现升高趋势。 相似文献
10.
This study has evaluated the possible role of serotonin, a potential morphogen, in the regulation of vasoactive intestinal polypeptide (VIP) gene expression in the target neurons of the suprachiasmatic nucleus (SCN) before and after the onset of the serotonin neurotransmitter function. VIP gene expression was quantified by in situ hybridization of the corresponding mRNA on cryostat sections with subsequent film autoradiography and densitometry. The content of VIP mRNA was measured in the SCN in fetuses at the 21st embryonic day (E21) and in postnatal rats at day 11 (P11) following chronic depletion of serotonin by p-chlorophenylalanine, an inhibitor of serotonin synthesis. This inhibitor was daily injected to pregnant rats for E13–20 or to postnatal animals for P2–10. Results of this study indicate that prenatal serotonin depletion caused a significant increase in VIP mRNA content in the SCN compared to control fetuses. On the contrary, the same treatment performed postnatally did not change VIP mRNA levels in the SCN. These data suggest that the VIP gene expression in differentiating target neurons of the SCN might be under serotonin inhibitory control during prenatal neurogenesis, prior to the onset of the serotoninergic neurotransmission. 相似文献