Uraki Misato, Kawase Atsushi, Matsushima Yuka, Iwaki Masahiro
Department of Pharmacy, School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashiosaka, Osaka, 577-8502, Japan.
Eur J Drug Metab Pharmacokinet. 2016 Jun;41(3):301-7. doi: 10.1007/s13318-015-0259-4. Epub 2015 Feb 6.
An in situ perfused rat liver system is useful for studying the hepatic disposition of drugs and their metabolites. However, the effects of the perfusion conditions on drug disposition are unclear. We examined the effects of conditions such as flow rate (13 or 26 mL/min) and bile acid on disposition of diclofenac (DF) as a model drug and DF metabolites [diclofenac-1-O-acyl glucuronide (DF-Glu) or 4'-hydroxydiclofenac (DF-4'OH)] in the absence of albumin. DF, DF-Glu, and DF-4'OH concentrations in the perfusate and cumulative amounts of DF-Glu excreted in bile were measured using high-performance liquid chromatography methods. DF in the perfusate was rapidly eliminated as the perfusate flow rate increased. The area under the plasma concentration-time curve from 0 to 60 min (AUC0-60) for DF-Glu and DF-4'OH in a perfusate containing bile acid was lower at a flow rate of 26 and 13 mL/min, respectively. The bile flow rate at 26 mL/min with 24 μM of bile acid in the perfusate was significantly higher (ca. 3.5 times) compared with that at 13 mL/min without bile acid. Cumulative biliary DF-Glu excretion was also dramatically affected by the flow rate and addition of bile acid. This study indicated that the flow rate and bile acid in the perfused rat liver were key factors for bile flow rate and DF, DF-Glu, and DF-4'OH disposition in the absence of albumin.
原位灌注大鼠肝脏系统对于研究药物及其代谢产物的肝脏处置情况很有用。然而，灌注条件对药物处置的影响尚不清楚。我们研究了流速（13或26 mL/min）和胆汁酸等条件对作为模型药物的双氯芬酸（DF）及其代谢产物[双氯芬酸-1-O-酰基葡萄糖醛酸苷（DF-Glu）或4'-羟基双氯芬酸（DF-4'OH）]在无白蛋白情况下处置的影响。使用高效液相色谱法测量灌注液中DF、DF-Glu和DF-4'OH的浓度以及胆汁中排泄的DF-Glu的累积量。随着灌注液流速增加，灌注液中的DF迅速消除。在含有胆汁酸的灌注液中，DF-Glu和DF-4'OH在0至60分钟的血浆浓度-时间曲线下面积（AUC0-60）分别在流速为26和13 mL/min时较低。灌注液中含有24 μM胆汁酸、流速为26 mL/min时的胆汁流速比无胆汁酸、流速为13 mL/min时显著更高（约3.5倍）。流速和胆汁酸的添加对胆汁中DF-Glu的累积排泄也有显著影响。本研究表明，在无白蛋白的情况下，灌注大鼠肝脏中的流速和胆汁酸是胆汁流速以及DF、DF-Glu和DF-4'OH处置的关键因素。
