Weber S J, Greene D L, Hruby V J, Yamamura H I, Porreca F, Davis T P
Department of Pharmacology, University of Arizona College of Medicine, Tucson.
J Pharmacol Exp Ther. 1992 Dec;263(3):1308-16.
The route of administration of a given drug can have a significant influence upon whole body distribution. The present study examined whole body distribution of the delta opioid receptor-selective peptide [3H]DPDPE in male CD1 mice after administration by several routes. Additionally, we describe regional brain distribution of [3H]DPDPE after i.v. administration with and without pretreatment with naloxone or the selective delta receptor antagonist naltrindole. Finally, characterization of the inherent enzymatic stability of DPDPE was also examined. Intravenous administration results in a significantly large amount of [3H]DPDPE in the small intestine and flush at 15 and 30 min postadministration, suggesting rapid biliary excretion. The highest level in the brain after i.v. administration occurred at 60 min (0.08%). After i.p. and s.c. administration, large amounts of [3H]DPDPE were found in the small intestine and flush, but not until 60 min postadministration, suggesting a slower rate of absorption from the site of administration. The i.p. and s.c. groups' brain levels peaked at 120 min (0.07 and 0.09%, respectively). The highest levels in the brain after p.o. administration were seen at 240 min (0.03%). Examination of regional brain distribution data showed no significant difference in the levels of [3H]DPDPE between brain regions at any time point studied. However, naloxone pretreatment resulted in significant reductions of [3H]DPDPE in all brain regions at 5 and 10 min. Naltrindole pretreatment resulted in significant reductions in the frontal cortex and striatum at 5 and/or 10 min postadministration, but had no effect on [3H]DPDPE levels in cerebellum, hippocampus or brain stem.(ABSTRACT TRUNCATED AT 250 WORDS)
某种特定药物的给药途径可对其在全身的分布产生重大影响。本研究检测了δ阿片受体选择性肽[³H]DPDPE经多种途径给药后在雄性CD1小鼠体内的全身分布情况。此外，我们还描述了静脉注射[³H]DPDPE且预先用纳洛酮或选择性δ受体拮抗剂纳曲吲哚预处理及未预处理时其在脑内的区域分布情况。最后，还检测了DPDPE内在酶稳定性的特征。静脉注射后，在给药后15分钟和30分钟时，小肠和排泄物中出现大量[³H]DPDPE，提示胆汁排泄迅速。静脉注射后60分钟时脑内达到最高水平（0.08%）。腹腔注射和皮下注射后，在小肠和排泄物中发现大量[³H]DPDPE，但直到给药后60分钟才出现，提示从给药部位的吸收速率较慢。腹腔注射组和皮下注射组脑内水平在120分钟时达到峰值（分别为0.07%和0.09%）。口服给药后，在240分钟时脑内达到最高水平（0.03%）。对脑内区域分布数据的检测显示，在所研究的任何时间点，脑区之间[³H]DPDPE水平均无显著差异。然而，纳洛酮预处理导致在5分钟和10分钟时所有脑区的[³H]DPDPE显著降低。纳曲吲哚预处理导致给药后5分钟和/或10分钟时额叶皮质和纹状体中[³H]DPDPE显著降低，但对小脑、海马或脑干中的[³H]DPDPE水平无影响。（摘要截选至250字）
