Research and Technology Directorate, Combat Capabilities Development Command Chemical Biological Center, U. S. Army, Aberdeen Proving Ground, MD, 21010-5424, United States.
Research and Technology Directorate, Combat Capabilities Development Command Chemical Biological Center, U. S. Army, Aberdeen Proving Ground, MD, 21010-5424, United States.
Toxicol Lett. 2021 Jun 1;343:28-33. doi: 10.1016/j.toxlet.2021.02.017. Epub 2021 Feb 27.
Carfentanil is an ultra-potent opioid with an analgesic potency 10,000 times that of morphine but has received little scientific investigation. In the present study, the human cytochrome P450 (CYP) isozymes catalyzing the oxidative metabolism of carfentanil were investigated. Using UHPLC-HRMS, Michaelis-Menten kinetics of formation for three major metabolites norcarfentanil (M1), pharmaceutical active metabolite 4-[(1-oxopropyl)phenylamino]-1-(2-hydroxyl-2-phenylethyl)-4-piperidinecarboxylic acid methyl ester (M11), and 4-[(1-oxopropyl)phenylamino]-1-(2-oxo-2-phenylethyl)-4-piperidinecarboxylic acid methyl ester (M15) were determined. Isozymes catalyzing the formation of the low abundant, highly active metabolite 1-[2-(2-hydroxylphenyl)ethyl]-4-[(1-oxopropyl)phenylamino]-4-piperidinecarboxylic acid methyl ester (M13) were also identified. Selective P450 inhibition studies with pooled human liver microsomes (HLMs) and recombinant CYP isozymes suggested that metabolites M1, M11, and M15 were predominantly formed by isozyme CYP3A5, followed by CYP3A4. Isozymes CYP2C8 and CYP2C9 also made contributions but to a much lesser extent. Highly potent metabolite M13 was predominantly formed by isozyme CYP2C9, followed by CYP2C8. These findings indicate that CYP3A5, CYP3A4, CYP2C8 and CYP2C9 play a major role in the transformation of carfentanil to M1 (norcarfentanil), M11, M13 and M15 through N-dealkylation of piperidine ring, hydroxylation of phenethyl group and ketone formation on phenethyl linker by human liver micrsomes.
卡芬太尼是一种超强效阿片类药物，其镇痛效力是吗啡的 10000 倍，但几乎没有科学研究。本研究旨在探讨人细胞色素 P450（CYP）同工酶对卡芬太尼氧化代谢的催化作用。采用 UHPLC-HRMS 法，测定了三种主要代谢物去甲卡芬太尼（M1）、药物活性代谢物 4-[(1-氧代丙基)苯基氨基]-1-(2-羟基-2-苯乙基)-4-哌啶羧酸甲酯（M11）和 4-[(1-氧代丙基)苯基氨基]-1-(2-氧代-2-苯乙基)-4-哌啶羧酸甲酯（M15）形成的米氏动力学。还鉴定了催化低丰度、高活性代谢物 1-[2-(2-羟基苯基)乙基]-4-[(1-氧代丙基)苯基氨基]-4-哌啶羧酸甲酯（M13）形成的同工酶。采用人肝微粒体（HLM）和重组 CYP 同工酶的选择性 P450 抑制研究表明，代谢物 M1、M11 和 M15 主要由同工酶 CYP3A5 形成，其次是 CYP3A4。同工酶 CYP2C8 和 CYP2C9 也有一定贡献，但贡献较小。高活性代谢物 M13 主要由同工酶 CYP2C9 形成，其次是 CYP2C8。这些发现表明，CYP3A5、CYP3A4、CYP2C8 和 CYP2C9 通过人肝微粒体中环丙啶环 N-脱烷基化、苯乙基侧链羟基化和酮形成，在卡芬太尼转化为 M1（去甲卡芬太尼）、M11、M13 和 M15 中发挥主要作用。
