绝对生物利用度的上限一般多大啊？我做了几个药都超过100%，有的甚至达130%，不晓得哪的问题，愁死了，高手们指点下
最大100%，我也做过超的，后来重做了
楼主的剂量多少？是否现用现配？动物种属？给药途径？不同给药途径是否同一人同日进行？是否从同一瓶子中取药或是经稀释得到的不同瓶子？申报还是药筛？
排除操作失误的话，这种情况应该多发于生物利用度高的小鼠PK实验，因为小鼠试验不能用同一个体取得完整曲线，给药体积小造成给药误差大。比如2只小鼠，tmax分别是2和4h，恰巧分别取到它们的tmax，那AUC岂不是偏大
用的是SD大鼠，用来筛选的。IV是1 mg/mL,PO是5 mg/mL,现用现配，同人同日操作，同一管给的药，澄清。
建议对两种Formulation用working solution进行定量。
假如口服formulation的浓度偏高，可以用校正剂量计算绝对生物利用度。
假如不偏高，再继续寻找原因。
有没有想过肠肝循环等“再利用”的原因？
我也遇到类似的情况，我是药物筛选阶段遇到的此类情况，我觉得原因可能是由于非线性动力学造成的，由于iv和po的剂量不同，如果po组，AUC随剂量超比例增长，遇到觉对BA比较高的化合物，可能会出现此类问题
不是线性动力学特征，把你的口服弄成1 mg的剂量做，估计结果更真实
如果是肝肠循环造成的，增加采血密度可以解决的。5mg/kg口服非线性概率不大。“同一管给的药”的意思是从同一个容器取的药吧？如果是的话，那分析formulation也是解决不了的。其实稍微超一点对于药筛问题不大，毕竟不是同一个大鼠的IV和PO，分布体积的个体差异也是可能造成这种现象的，不知道楼主用的大鼠体重多少，差异大不大
老鼠差异也不大180-210之间
把你的数据贴出来卡看，原始数据
p.o. 组和 i.v. 组设置相同的剂量，再重新做一遍，这样拿到的结果最有说服力，否则只是这样讨论，意义不大
Reasons to have >100% bioavailability for an NCE
The following message was posted to: PharmPKDear Ramesh,In the present day scenario, poor oral bioavailability (BA) has been an industry wide problem owing to increasingly lipophilic compounds (with poor aqueous solubility) emerging from drug discovery programs. In this scenario, your issue of greater than 100% BA, although requires probing, is something that everyone loves to have! While there could be various different reasons for >100% oral BA, I guess it is important to confirm that the doses administered are what you actually intended before probing too much into this issue. You may have already looked into this, but it is worth double checking the actual concentration of formulation, volume of dose administered and, if you administer aliquot from a bulk formulation, the homogeneity of formulation and hence the uniformity of the doses administered. If none of these are issues and if the BA is significantly higher than 100% and show increasing trend with increasing oral dose, then the issue is worth probing! As the oral BA of a compound depends on the extent of absorption, distribution and elimination, it is important to know which of these processes are responsible for >100% BA. From the information given I guess there are no issues with respect to 'absorption' (as oral BA is100% at 3 mg/kg) and solubility (in which case you should see decreased BA with increase in the oral dose). Also, the fact that the Cmax is dose proportional also suggests that absorption is not solubility limited and, probably, no changes in the extent of 'distribution'. What remains is the 'elimination', the major determinants of which are metabolism(liver/intestinal), biliary excretion (parent or conjugated metabolite)and excretion of the intact compound into the urine along with any involvement of transporters in these processes. Saturation of intestinal efflux/metabolism at higher doses could sometimes enhance oral BA, but as you have BA of 100% at the lowest oraldose, I imagine, this may not be an issue in your case. I am not sure how big your NCE compound to be a candidate for excretion into bile 'neat' and if there are any metabolically labile groups for direct PhaseII conjugation making it a substrate for biliary transporters. If the biliary excretion of the compound through bile is high, then this could lead to significant entero-hepatic recirculation (EHR). If this is the case this could lead to repeated absorption of the same drug leading to enhanced AUC and hence %BA (Is 100% BA at lowest oral dose due to the EHR rather than complete absorption!?) Alternatively, if the NCE is a substrate for sinusoidal (blood side) uptake transporters in the liver, saturation of this process at high concentration would lower entry into hepatocyte and therefore lower liver metabolism. If this is the case plasma concentration of the parent (metabolite to parent ratio decreases) would increase which again result in higher %BA. However, if the compound is substrate of canalicular (bile side) efflux transporters and if this process saturates at high concentrations, the resulting effect would depend on the extent of metabolism and its interplay with efflux which could result in all possible observations (i.e. no effect, decrease or increase in the AUC of parent). Finally, if the excretion into urine is an active process, saturation of this at higher doses could result in more than proportional increase in AUC. If this is the case and if you have monitored urinary excretion of the parent, the % of dose excreted into urine should decrease with increasing dose. So, there are numerous reasons for such an observation and the interplay of different events makes things even more complex. In such a scenarioit is important not to jump to any conclusions based on a certain observation as it is possible that the particular observation could be a net effect of 2 or more opposing events. The best thing to do in such situations is to monitor the mass balance and see where the compound is going and if most of the dose administered is accountable. It is not possible to draw definitive conclusions if a major part of the dose is unaccountable! Hope this longwinded response answers your query. Cheers! Kasiram. 2 1 2 下一页 尾页
最大100%，我也做过超的，后来重做了
楼主的剂量多少？是否现用现配？动物种属？给药途径？不同给药途径是否同一人同日进行？是否从同一瓶子中取药或是经稀释得到的不同瓶子？申报还是药筛？
排除操作失误的话，这种情况应该多发于生物利用度高的小鼠PK实验，因为小鼠试验不能用同一个体取得完整曲线，给药体积小造成给药误差大。比如2只小鼠，tmax分别是2和4h，恰巧分别取到它们的tmax，那AUC岂不是偏大
用的是SD大鼠，用来筛选的。IV是1 mg/mL,PO是5 mg/mL,现用现配，同人同日操作，同一管给的药，澄清。
建议对两种Formulation用working solution进行定量。
假如口服formulation的浓度偏高，可以用校正剂量计算绝对生物利用度。
假如不偏高，再继续寻找原因。
有没有想过肠肝循环等“再利用”的原因？
我也遇到类似的情况，我是药物筛选阶段遇到的此类情况，我觉得原因可能是由于非线性动力学造成的，由于iv和po的剂量不同，如果po组，AUC随剂量超比例增长，遇到觉对BA比较高的化合物，可能会出现此类问题
不是线性动力学特征，把你的口服弄成1 mg的剂量做，估计结果更真实
如果是肝肠循环造成的，增加采血密度可以解决的。5mg/kg口服非线性概率不大。“同一管给的药”的意思是从同一个容器取的药吧？如果是的话，那分析formulation也是解决不了的。其实稍微超一点对于药筛问题不大，毕竟不是同一个大鼠的IV和PO，分布体积的个体差异也是可能造成这种现象的，不知道楼主用的大鼠体重多少，差异大不大
老鼠差异也不大180-210之间
把你的数据贴出来卡看，原始数据
p.o. 组和 i.v. 组设置相同的剂量，再重新做一遍，这样拿到的结果最有说服力，否则只是这样讨论，意义不大
Reasons to have >100% bioavailability for an NCE
The following message was posted to: PharmPKDear Ramesh,In the present day scenario, poor oral bioavailability (BA) has been an industry wide problem owing to increasingly lipophilic compounds (with poor aqueous solubility) emerging from drug discovery programs. In this scenario, your issue of greater than 100% BA, although requires probing, is something that everyone loves to have! While there could be various different reasons for >100% oral BA, I guess it is important to confirm that the doses administered are what you actually intended before probing too much into this issue. You may have already looked into this, but it is worth double checking the actual concentration of formulation, volume of dose administered and, if you administer aliquot from a bulk formulation, the homogeneity of formulation and hence the uniformity of the doses administered. If none of these are issues and if the BA is significantly higher than 100% and show increasing trend with increasing oral dose, then the issue is worth probing! As the oral BA of a compound depends on the extent of absorption, distribution and elimination, it is important to know which of these processes are responsible for >100% BA. From the information given I guess there are no issues with respect to 'absorption' (as oral BA is100% at 3 mg/kg) and solubility (in which case you should see decreased BA with increase in the oral dose). Also, the fact that the Cmax is dose proportional also suggests that absorption is not solubility limited and, probably, no changes in the extent of 'distribution'. What remains is the 'elimination', the major determinants of which are metabolism(liver/intestinal), biliary excretion (parent or conjugated metabolite)and excretion of the intact compound into the urine along with any involvement of transporters in these processes. Saturation of intestinal efflux/metabolism at higher doses could sometimes enhance oral BA, but as you have BA of 100% at the lowest oraldose, I imagine, this may not be an issue in your case. I am not sure how big your NCE compound to be a candidate for excretion into bile 'neat' and if there are any metabolically labile groups for direct PhaseII conjugation making it a substrate for biliary transporters. If the biliary excretion of the compound through bile is high, then this could lead to significant entero-hepatic recirculation (EHR). If this is the case this could lead to repeated absorption of the same drug leading to enhanced AUC and hence %BA (Is 100% BA at lowest oral dose due to the EHR rather than complete absorption!?) Alternatively, if the NCE is a substrate for sinusoidal (blood side) uptake transporters in the liver, saturation of this process at high concentration would lower entry into hepatocyte and therefore lower liver metabolism. If this is the case plasma concentration of the parent (metabolite to parent ratio decreases) would increase which again result in higher %BA. However, if the compound is substrate of canalicular (bile side) efflux transporters and if this process saturates at high concentrations, the resulting effect would depend on the extent of metabolism and its interplay with efflux which could result in all possible observations (i.e. no effect, decrease or increase in the AUC of parent). Finally, if the excretion into urine is an active process, saturation of this at higher doses could result in more than proportional increase in AUC. If this is the case and if you have monitored urinary excretion of the parent, the % of dose excreted into urine should decrease with increasing dose. So, there are numerous reasons for such an observation and the interplay of different events makes things even more complex. In such a scenarioit is important not to jump to any conclusions based on a certain observation as it is possible that the particular observation could be a net effect of 2 or more opposing events. The best thing to do in such situations is to monitor the mass balance and see where the compound is going and if most of the dose administered is accountable. It is not possible to draw definitive conclusions if a major part of the dose is unaccountable! Hope this longwinded response answers your query. Cheers! Kasiram. 2 1 2 下一页 尾页