Leinweber F J, Szuna A J, Loh A C, Sepinwall J, Carter K, Schwartz M A
Biochem Pharmacol. 1982 Feb 15;31(4):553-9. doi: 10.1016/0006-2952(82)90159-9.
Analgesia and brain and plasma concentrations of (-)-3-phenoxy-N-methylmorphinan (PMM) and its metabolites were determined in rats administered 50 mg/kg of 3H-labeled PMM p.o., an approximate ED50. Unchanged PMM and two active metabolites, levorphanol and a different phenol, p-hydroxylated on the 3-phenoxy group (pOH-PMM), were present in brain at concentrations greater than in plasma. Analgesia was observed from 1 to 6 hr and was associated with brain concentrations of 400-1400 ng/g of PMM, 190-300 ng/g of pOH-PMM, and 16-27 ng/g of levorphanol. The presence of 58% of the administered dose as unchanged PMM in the gastrointestinal tract at 6 hr may reflect slow absorption and explain the persisting brain concentrations of PMM and its metabolites as well as the prolonged analgesia. Analgesia may have been due to the presence in brain of only PMM, pOH-PMM or levorphanol, or to the combined activity of two or three of these substances. Administration of the approximate ED50 of 3H-labeled levorphanol (0.1 mg/kg, s.c., or 6 mg/kg, p.o.) resulted in brain levorphanol concentrations (11-18 ng/g) close to those observed when PMM was administered p.o. at 50 mg/kg. After administration of an approximate subcutaneous ED50 of [3H]pOH-PMM of 24 mg/kg, the brains contained pOH-PMM (1500-4100 ng/g) and levorphanol (60-100 ng/g); these levorphanol concentrations were higher than those found after administration of the approximate ED50 of PMM or levorphanol. The findings indicate that brain levorphanol concentrations resulting from administration of PMM or pOH-PMM to rats may account for the analgesic activity observed, i.e. that PMM and pOH-PMM may act as prodrugs for levorphanol
给大鼠口服给予50mg/kg的3H标记的（-）-3-苯氧基-N-甲基吗啡喃（PMM）（约为半数有效剂量[ED50]），测定其镇痛效果以及脑和血浆中PMM及其代谢物的浓度。脑内未变化的PMM以及两种活性代谢物，左啡诺和一种在3-苯氧基上羟基化的不同酚类（对羟基-PMM）的浓度高于血浆中的浓度。在给药后1至6小时观察到镇痛效果，这与脑内PMM浓度为400 - 1400ng/g、对羟基-PMM浓度为190 - 300ng/g以及左啡诺浓度为16 - 27ng/g相关。在6小时时胃肠道中存在58%的给药剂量的未变化PMM，这可能反映了吸收缓慢，并解释了PMM及其代谢物在脑中持续存在的浓度以及延长的镇痛效果。镇痛作用可能是由于脑中仅存在PMM、对羟基-PMM或左啡诺，或者是由于这两种或三种物质的联合活性。给予约ED50的3H标记的左啡诺（0.1mg/kg，皮下注射，或6mg/kg，口服）后，脑内左啡诺浓度（11 - 18ng/g）接近口服给予50mg/kg PMM时观察到的浓度。给予约皮下ED50的[3H]对羟基-PMM 24mg/kg后，脑中含有对羟基-PMM（1500 - 4100ng/g）和左啡诺（60 - 100ng/g）；这些左啡诺浓度高于给予PMM或左啡诺的约ED50后发现的浓度。这些发现表明，给大鼠给予PMM或对羟基-PMM后脑中产生的左啡诺浓度可能解释了观察到的镇痛活性，即PMM和对羟基-PMM可能作为左啡诺的前体药物。
