The effect of ethanol on the metabolism of amphetamine by the rat
The effect of ethanol on the metabolism of amphetamine by the rat
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乙醇对大鼠苯丙胺代谢的影响
DOI：
10.1111/j.2042-7158.1969.tb08188.x
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发表时间：
1969
期刊：
影响因子：
--
通讯作者：
T. Barbee
中科院分区：
文献类型：
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作者：
P. Creaven;T. Barbee
在研究乙醇对胺代谢影响的过程中，我们研究了乙醇预处理对(I)-[2-14C]苯丙胺代谢的影响。雄性SD大鼠150 g，饲养在代谢笼中，用25%乙醇溶液(v/v)经胃管注射乙醇5 g/kg，30分钟后给予(&)-[2-14C]苯丙胺(1*6 mci/mmo1)，5 mg/kg，加入0.5ml等渗盐水中。对照组动物经胃管注入适量等渗盐水和相同剂量的(*)-[2-14C]硫酸阿麻酚胺。排尿后立即测定尿液pH值，冰冻尿液。乙醇处理不改变尿液pH值(5-5-6.8)。尿液在Whatman 3 mm纸板上以正丁醇-冰醋酸-水(4：1：1v/v)为流动相，异丙醇-氨-水(8：1：1v/v)为流动相。通过放射自显影定位的代谢物被取出，并在Packard Model 3375型液体闪烁计数器中进行放射性计数。苯丙胺、对羟基苯丙胺和对羟基苯丙胺葡萄糖醛酸脂占尿放射性的85%以上。尿液经β-葡萄糖苷酸酶处理后，用Axelrod(1954)法测定苯丙胺和总对羟基苯丙胺的含量。苯丙胺的测定采用同位素稀释重结晶恒定比活度的方法。对羟基苯丙胺葡萄糖醛酸苷的鉴定是通过用/L葡萄糖醛酸酶将洗脱液定量转化为对羟基苯丙胺来确认的。对照组和乙醇处理组动物在服用苯丙胺后24小时内尿液放射性恢复的平均值均为77%。经乙醇处理后，尿中以苯丙胺形式存在的放射性百分率显著增加，以游离和结合形式存在的对羟基苯丙胺显著减少：对羟基苯丙胺(P<；0.005)的对照和乙醇预处理值分别为16.5±5.28和65.4~6.91；对羟基苯丙胺(P<；0.005)分别为7.3f3.60和2.4f1.49；每组以游离态排泄的对羟基苯丙胺的比例(约占总对羟基苯丙胺的10%)是相同的。乙醇预处理对去甲肾上腺素、5-羟色胺和酪胺的代谢模式有深远的影响(Davis，Brown等人，1967,1967a；Tacker，Creaven&McIsaac，1969)。然而，这些胺被单胺氧化酶脱胺，乙醇的作用是增加这样形成的中间醛的还原。苯丙胺在大鼠体内的代谢主要是通过苯环的羟化作用(Axelrod 1954)，因此乙醇不会对其代谢产生任何影响。乙醇对苯丙胺代谢的影响是特异性的，还是对芳香族羟化的普遍影响，以及这两种常见滥用药物的代谢相互作用是否也在人类中发生，目前尚不清楚，因为人类的苯丙胺代谢模式与大鼠的不同(Dring，Smith&Williams，1966)。这项工作得到了美国公共卫生服务基金MH 144340-2的支持。
In the course of an investigation into the effect of ethanol on the metabolism of amines we have studied the effect of pretreatment with ethanol on the metabolism of ( i)-[2-14C]amphetamine. Male Sprague-Dawley rats, 150 g, housed in metabolism cages received ethanol, 5 g/kg, as a 25% solution (v/v) by stomach tube followed 30 min later by ( &)-[2-14C]amphetamine sulphate (1 *6 mCi/mmol), 5 mg/kg, intraperitoneally in 0.5 ml of isotonic saline. Control animals received an appropriate volume of isotonic saline by stomach tube and the same dose of ( *)-[2-l4C]arnphetamine sulphate. The pH of the urine was measured immediately after voiding, and the urine frozen. The urinary pH (5-5-6.8) was not altered by ethanol treatment. Urine was chromatographed in two dimensions on Whatman 3MM paper in n-butanol -acetic acid-water (4 : 1 : 1 v/v> followed by isopropanol-ammonia-water (8 : 1 : 1 v/v). The metabolites, located by autoradiography, were cut out and the radioactivity counted in a Packard Model 3375 liquid scintillation counter. Amphetamine, p-hydroxyamphetamine and p-hydroxyamphetamine glucuronide accounted for over 85;/, of the urinary radioactivity. Amphetamine and total p-hydroxyamphetamine were also determined by the method of Axelrod (1954) after treatment of the urine with P-glucuronidase. Amphetamine was further determined by isotope dilution and recrystallization to constant specific activity. The identification of p-hydroxyamphetamine glucuronide was confirmed by hydrolysis of the eluate from chromatograms with /Lglucuronidase which converted it quantitatively to p-hydroxyamphetamine. Recovery of radioactivity in the urine in the first 24 h after dosing with amphetamine had a mean value of 77% for both control and ethanol-treated animals. The percentage of the urinary radioactivity present as amphetamine was greatly increased and that as free and conjugated p-hydroxyamphetamine greatly reduced by ethanol pretreatment : control and ethanol pretreated values being, respectively, 16.5 5.28 and 65.4 & 6.91 for amphetamine ( P t0.001); 7.3 f 3.60 and 2.4 f 1.49 for p-hydroxyamphetamine (P< 0.005) ; 61-8 & 4.04 and 20.9 & 5.99 for p-hydroxyamphetamine glucuronide ( P t0.001) (means for 6 animals & s.d.). The proportion of p-hydroxyamphetamine excreted in the free form (about 10% of the total p-hydroxyamphetamine) was the same in each group. Ethanol pretreatment has a profound effect on the pattern of metabolism of noradrenaline, 5-hydroxytryptamine and tyramine (Davis, Brown & others, 1967, 1967a; Tacker, Creaven & McIsaac, 1969). However, these amines are deaminated by monoamine oxidase and the effect of ethanol is to increase the reduction of the intermediate aldehyde so formed. Amphetamine is metabolized in the rat largely by hydroxylation of the benzene ring (Axelrod 1954) so that no effect of ethanol on its metabolism would be expected. Whether the observed effect of ethanol on amphetamine metabolism is specific or is a general effect on aromatic hydroxylation, and whether the metabolic interaction of these two commonly abused drugs occurs also in man, is still unknown since the pattern of amphetamine metabolism in man is different from that in the rat (Dring, Smith & Williams, 1966). This work was supported by grant MH 144340-2, U.S. Public Health Service.