Antonilli Letizia, Suriano Carmen, Paolone Giovanna, Badiani Aldo, Nencini Paolo
Vittorio Erspamer Department of Human Physiology and Pharmacology, University of Rome La Sapienza, Piazzale Aldo Moro 5, I-00185 Rome, Italy.
J Pharmacol Exp Ther. 2003 Nov;307(2):651-60. doi: 10.1124/jpet.103.055467. Epub 2003 Sep 15.
After absorption, heroin is transformed into mono-acetyl-morphine and then into morphine. Morphine, in turn, is metabolized to morphine-3-glucuronide (M3G), an inactive compound, and morphine-6-glucuronide (M6G), a potent opioid agonist. Thus, changes in the rate of formation of M6G may alter the pharmacological consequences of a treatment with heroin or morphine. In this study, we investigate the effect of repeated exposures (10 daily i.p. injections) to heroin, morphine, cadmium (which has been previously shown to inhibit M3G formation in vitro), or heroin + cadmium on morphine glucuronidation both in vivo and ex vivo (i.e., microsomal preparation obtained from rats treated in vivo). Repeated heroin (2.5, 5.0, and 10 mg/kg) increased plasma levels of M6G (which was undetectable in all other groups) and reduced those of M3G. Also, the microsomal preparations obtained from the liver of repeated heroin rats, when incubated with morphine, yielded significant amounts of M6G (which was undetectable in all other groups) and decreased levels of M3G relative to the control groups. These effects were reversible upon discontinuation of heroin administration. In contrast, repeated morphine (10, 20, and 40 mg/kg) only slightly reduced M3G formation at the dose of 40 mg/kg. Repeated cadmium (5, 15, and 45 microg/kg) reduced the rate of M3G formation without inducing M6G synthesis. The effects of the repeated coadministration of heroin (10 mg/kg) and cadmium (15 microg/kg) were virtually identical to those of repeated heroin alone. In summary, repeated exposure of rats to heroin can shift morphine glucuronidation toward the formation of the active metabolite M6G.
吸收后，海洛因转化为单乙酰吗啡，然后再转化为吗啡。吗啡继而代谢为无活性的化合物吗啡 - 3 - 葡萄糖醛酸苷（M3G）和强效阿片类激动剂吗啡 - 6 - 葡萄糖醛酸苷（M6G）。因此，M6G形成速率的变化可能会改变海洛因或吗啡治疗的药理后果。在本研究中，我们调查了反复暴露（每天腹腔注射10次）于海洛因、吗啡、镉（先前已证明其在体外可抑制M3G形成）或海洛因 + 镉对体内和体外吗啡葡萄糖醛酸化的影响（即从体内处理的大鼠获得的微粒体制剂）。反复给予海洛因（2.5、5.0和10 mg/kg）可提高血浆中M6G的水平（在所有其他组中均检测不到）并降低M3G的水平。此外，从反复给予海洛因的大鼠肝脏获得的微粒体制剂，与吗啡一起孵育时，产生了大量的M6G（在所有其他组中均检测不到），并且相对于对照组，M3G的水平降低。停止给予海洛因后，这些影响是可逆的。相比之下，反复给予吗啡（10、20和40 mg/kg）仅在剂量为40 mg/kg时略微降低了M3G的形成。反复给予镉（5、15和45 μg/kg）降低了M3G的形成速率，但未诱导M6G的合成。反复联合给予海洛因（10 mg/kg）和镉（15 μg/kg）的效果与单独反复给予海洛因的效果几乎相同。总之，大鼠反复暴露于海洛因可使吗啡葡萄糖醛酸化朝着活性代谢物M6G的形成方向转变。
