Le Guellec C, Lacarelle B, Villard P H, Point H, Catalin J, Durand A
Laboratoire de Pharmacocinétique et Toxicocinétique, Faculté de Pharmacie, Marseille, France.
Anesth Analg. 1995 Oct;81(4):855-61. doi: 10.1097/00000539-199510000-00034.
This in vitro study was conducted to evaluate propofol glucuronidation and the effect of concomitantly administered drugs in various species. Propofol glucuronidation was studied in microsomal fractions from rat, rabbit, and human livers. Extrahepatic metabolism was investigated using lung and kidney microsomes. The propofol-uridine diphosphate-glucuronosyltransferase (UGT) activity measured in liver microsomes was higher in rabbit than in rat. Among the three tested species, human livers exhibited the highest activity, with only small variability in the three samples studied. Animal kidney, but not lung (animal or human), microsomes were able to glucuronidate propofol, meaning that extrahepatic metabolism of propofol exists, at least in the kidney, in the tested species (rat and rabbit). Since metabolic interactions are potential sources of prolonged drug effect or overdose, we screened the effect of 21 compounds (known substrates of various UGT or potentially coadministered drugs) on the glucuronidation of propofol by human liver microsomes. Inhibitions obtained with chemicals or drugs glucuronidated by either UGT1 or UGT2 families (1-naphtol, 4-hydroxybiphenyl, carvacrol, n-propylgallate, ketoprofen, chloramphenicol, acetylsalicylic acid) indicated that at least two UGT isoforms are involved in propofol glucuronidation. Inhibition was observed with several drugs potentially coadministered during pre-, per, or postoperative periods (e.g., acetylsalicyclic acid, ketoprofen, oxazepam, fentanyl). Although not directly transposable to the in vivo situation, these results indicate that such interactions are theoretically possible.(ABSTRACT TRUNCATED AT 250 WORDS)
本体外研究旨在评估丙泊酚葡萄糖醛酸化作用以及同时给药的药物在不同物种中的影响。在大鼠、兔子和人类肝脏的微粒体组分中研究了丙泊酚葡萄糖醛酸化。使用肺和肾微粒体研究了肝外代谢。在肝脏微粒体中测得的丙泊酚 - 尿苷二磷酸 - 葡萄糖醛酸基转移酶（UGT）活性，兔子高于大鼠。在所测试的三个物种中，人类肝脏表现出最高活性，在所研究的三个样本中仅有很小的变异性。动物肾脏微粒体（而非肺微粒体，无论是动物还是人类的）能够使丙泊酚葡萄糖醛酸化，这意味着在所测试的物种（大鼠和兔子）中，至少在肾脏中存在丙泊酚的肝外代谢。由于代谢相互作用是药物作用延长或过量的潜在来源，我们筛选了21种化合物（各种UGT的已知底物或可能同时给药的药物）对人肝微粒体中丙泊酚葡萄糖醛酸化的影响。用UGT1或UGT2家族葡萄糖醛酸化的化学物质或药物（1 - 萘酚、4 - 羟基联苯、香芹酚、正丙基没食子酸、酮洛芬、氯霉素、乙酰水杨酸）获得的抑制作用表明，至少两种UGT同工酶参与丙泊酚葡萄糖醛酸化。在术前、术中或术后可能同时给药的几种药物（如乙酰水杨酸、酮洛芬、奥沙西泮、芬太尼）中观察到了抑制作用。尽管这些结果不能直接类推到体内情况，但表明这种相互作用在理论上是可能的。（摘要截选至250字）
