Early Origins of Adult Health Research Group, University of South Australia, Adelaide, Australia.
Health and Biomedical Innovation, University of South Australia, Adelaide, Australia.
PLoS One. 2020 May 12;15(5):e0233010. doi: 10.1371/journal.pone.0233010. eCollection 2020.
Methamphetamine use has increased over the past decade and the first use of methamphetamine is most often when women are of reproductive age. Methamphetamine accumulates in the liver; however, little is known about the effect of methamphetamine use on hepatic drug metabolism. Methamphetamine was administered on 3 occassions to female Dunkin Hartley guinea pigs of reproductive age, mimicking recreational drug use. Low doses of test drugs caffeine and midazolam were administered after the third dose of methamphetamine to assess the functional activity of cytochrome P450 1A2 and 3A, respectively. Real-time quantitative polymerase chain reaction was used to quantify the mRNA expression of factors involved in glucocorticoid signalling, inflammation, oxidative stress and drug transporters. This study showed that methamphetamine administration decreased hepatic CYP1A2 mRNA expression, but increased CYP1A2 enzyme activity. Methamphetamine had no effect on CYP3A enzyme activity. In addition, we found that methamphetamine may also result in changes in glucocorticoid bioavailability, as we found a decrease in 11β-hydroxysteroid dehydrogenase 1 mRNA expression, which converts inactive cortisone into active cortisol. This study has shown that methamphetamine administration has the potential to alter drug metabolism via the CYP1A2 metabolic pathway in female guinea pigs. This may have clinical implications for drug dosing in female methamphetamine users of reproductive age.
在过去的十年中，甲基苯丙胺的使用有所增加，而女性处于生育年龄时，首次使用甲基苯丙胺的情况最为常见。甲基苯丙胺在肝脏中积累；然而，人们对甲基苯丙胺使用对肝药物代谢的影响知之甚少。本研究模拟娱乐性药物使用，给处于生育年龄的雌性 Dunkin Hartley 豚鼠 3 次施用低剂量的甲基苯丙胺，以评估细胞色素 P450 1A2 和 3A 的功能活性。在第三次给予甲基苯丙胺后给予低剂量测试药物咖啡因和咪达唑仑，以分别评估细胞色素 P450 1A2 和 3A 的功能活性。实时定量聚合酶链反应用于定量与糖皮质激素信号、炎症、氧化应激和药物转运蛋白相关的因素的 mRNA 表达。本研究表明，甲基苯丙胺给药降低了肝 CYP1A2 mRNA 表达，但增加了 CYP1A2 酶活性。甲基苯丙胺对 CYP3A 酶活性没有影响。此外，我们发现甲基苯丙胺还可能导致糖皮质激素生物利用度的变化，因为我们发现 11β-羟类固醇脱氢酶 1 mRNA 表达减少，该酶将无活性的可的松转化为有活性的皮质醇。本研究表明，甲基苯丙胺给药有可能通过雌性豚鼠 CYP1A2 代谢途径改变药物代谢。这可能对处于生育年龄的女性甲基苯丙胺使用者的药物剂量产生临床影响。
