Aasmundstad T A, Mørland J
National Institute of Forensic Toxicology, Oslo, Norway.
Pharmacol Toxicol. 1998 Jun;82(6):272-9. doi: 10.1111/j.1600-0773.1998.tb01573.x.
The influence of ranitidine on morphine metabolism, with special emphasise on the ratio between morphine-3-glucuronide and morphine-6-glucuronide was studied in isolated guinea pig hepatocytes. Ranitidine reduced the Kel of morphine dose-dependently with a maximum effect of 50%, and increased the relative concentration of morphine-6-glucuronide to morphine-3-glucuronide. These effects could be due to a direct or indirect effect on the conjugation enzymes involved, or an effect on the transport of morphine or glucuronides across cell membranes. The latter explanation was rejected on the basis of the observation that the ratios between intra- and extracellular concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide were not influenced by ranitidine. Increasing concentrations of ranitidine gradually decreased the morphine-3-glucuronide/morphine-6-glucuronide ratio by up to 21%. This could stem from interference of energy or co-substrate supply, or through direct effects on the different UDPGTases involved. The observation that the present effect on morphine glucuronidation was the opposite of that observed when administering a known co-substrate (UDPGA) depletor, indicated that in all probability the effect of ranitidine was a direct inhibition on the uridine 5'-diphosphate glucuronyltransferases involved, with a more pronounced effect for the isoenzymes responsible for the 3'-glucuronidation.
在分离的豚鼠肝细胞中研究了雷尼替丁对吗啡代谢的影响，特别强调了吗啡 -3-葡萄糖醛酸苷与吗啡 -6-葡萄糖醛酸苷之间的比例。雷尼替丁剂量依赖性地降低吗啡的消除速率常数（Kel），最大效应为50%，并增加吗啡 -6-葡萄糖醛酸苷与吗啡 -3-葡萄糖醛酸苷的相对浓度。这些效应可能是由于对相关结合酶的直接或间接作用，或者是对吗啡或葡萄糖醛酸苷跨细胞膜转运的影响。基于雷尼替丁不影响细胞内和细胞外吗啡、吗啡 -3-葡萄糖醛酸苷和吗啡 -6-葡萄糖醛酸苷浓度之间的比例这一观察结果，排除了后一种解释。雷尼替丁浓度增加会使吗啡 -3-葡萄糖醛酸苷/吗啡 -6-葡萄糖醛酸苷的比例逐渐降低，降幅高达21%。这可能源于能量或共底物供应的干扰，或者是对所涉及的不同尿苷二磷酸葡萄糖醛酸基转移酶（UDPGTases）的直接作用。当前对吗啡葡萄糖醛酸化的影响与给予已知共底物（UDPGA）消耗剂时观察到的相反，这一观察结果表明，雷尼替丁的作用很可能是对所涉及的尿苷5'-二磷酸葡萄糖醛酸基转移酶的直接抑制，对负责3'-葡萄糖醛酸化的同工酶的影响更为明显。
