Chenery R J, Ayrton A, Oldham H G, Standring P, Norman S J, Seddon T, Kirby R
Drug Metab Dispos. 1987 May-Jun;15(3):312-7.
Diazepam metabolism has been investigated in cultured hepatocytes from rat, rabbit, dog, guinea pig, and man. The metabolite profile obtained by HPLC analysis of the culture medium indicated that substantial differences exist corresponding to known species differences in the metabolite profile of diazepam in vivo. These differences were attributed to a combination of the rate at which a metabolite was formed and the rate at which it is removed from the medium by further metabolism. The intrinsic clearance of nordiazepam in hepatocytes from each of the species exhibited the most marked species variation (rat much greater than guinea pig greater than rabbit greater than human greater than dog). Species that exhibited a high intrinsic clearance for nordiazepam were also those species that exhibited significant hydroxylation at the 4'-site of the molecule. The disappearance of diazepam was rapid in rat, dog, and guinea pig hepatocytes, but slow in human hepatocytes. Moreover, rat and human hepatocytes exhibited different saturability of diazepam clearance with respect to diazepam concentration accounting, at least in part, for the different rates of diazepam metabolism in the different species. These results support the value of hepatocytes in drug metabolism studies and especially in studies of species differences in metabolism.
已在来自大鼠、兔子、狗、豚鼠和人类的培养肝细胞中研究了地西泮的代谢情况。通过对培养基进行高效液相色谱分析得到的代谢产物谱表明，其与地西泮在体内代谢产物谱中已知的物种差异相对应，存在显著差异。这些差异归因于代谢产物形成的速率以及通过进一步代谢从培养基中去除的速率的综合作用。每种物种的肝细胞中去甲地西泮的内在清除率表现出最显著的物种差异（大鼠远大于豚鼠大于兔子大于人类大于狗）。对去甲地西泮表现出高内在清除率的物种也是那些在分子的4'-位点表现出显著羟基化的物种。地西泮在大鼠、狗和豚鼠肝细胞中的消失很快，但在人类肝细胞中很慢。此外，大鼠和人类肝细胞在地西泮清除率相对于地西泮浓度的饱和性方面表现不同，这至少部分解释了不同物种中地西泮代谢速率的差异。这些结果支持了肝细胞在药物代谢研究中的价值，特别是在代谢物种差异研究中的价值。
