Daniel W A, Syrek M, Ryłko Z, Kot M
Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Kraków.
Pol J Pharmacol. 2001 Nov-Dec;53(6):615-21.
The primary metabolic pathways of caffeine are 3-N-demethylation to paraxanthine (CYP1A2), 1-N-demethylation to theobromine and 7-N-demethylation to theophylline (CYP1A2 and other enzymes), and 8-hydroxylation to 1,3,7-trimethyluric acid (CYP3A). The aim of the present study was to investigate the influence of phenothiazine neuroleptics (chlorpromazine, levomepromazine, thioridazine, perazine) on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that all the investigated neuroleptics competitively inhibited caffeine oxidation in the rat liver, though their potency to inhibit particular metabolic pathways was not equal. Levomepromazine exerted the most potent inhibitory effect on caffeine oxidation pathways, the effect on 8-hydroxylation being the most pronounced. This indicates inhibition of CYP 1 A2 (inhibition of 3-N- and 1-N-demethylation; Ki = 36 and 32 microM, respectively), CYP3A2 (inhibition of 8-hydroxylations; Ki = 20 microM), and possibly other CYP isoenzymes (inhibition of 7-N-demethylation; Ki = 58 microM) by the neuroleptics. The potency of inhibition of caffeine oxidation by perazine was similar to levomepromazine. Thioridazine was a weaker inhibitor of caffeine 3-N- and 7-N-demethylation, while chlorpromazine was weaker in inhibiting caffeine 1-N- and 7-N-demethylation, compared to levomepromazine. In summary, the obtained results showed that all the investigated neuroleptics had a broad spectra of CYP inhibition in the rat liver. The isoenzymes CYP1A2 and CYP3A2 were distinctly inhibited by all the investigated neuroleptics, while other CYP isoenzymes (CYP2B and/or 2E1) by perazine and levomepromazine. The CYP3A2 inhibition was most pronounced. (Ki = 20-40 microM).
咖啡因的主要代谢途径包括通过细胞色素P450 1A2（CYP1A2）将其3 - N位去甲基化生成对黄嘌呤，1 - N位去甲基化生成可可碱，7 - N位去甲基化生成茶碱（CYP1A2及其他酶），以及通过CYP3A将其8 - 羟基化生成1,3,7 - 三甲基尿酸。本研究的目的是通过测定大鼠肝微粒体中咖啡因氧化来研究吩噻嗪类抗精神病药（氯丙嗪、左美丙嗪、硫利达嗪、奋乃静）对细胞色素P - 450活性的影响。所得结果表明，所有研究的抗精神病药均能竞争性抑制大鼠肝脏中的咖啡因氧化，尽管它们抑制特定代谢途径的效力并不相同。左美丙嗪对咖啡因氧化途径的抑制作用最强，对8 - 羟基化的影响最为显著。这表明抗精神病药对CYP 1 A2（抑制3 - N - 和1 - N - 去甲基化；Ki分别为= 36和32 microM）、CYP3A2（抑制8 - 羟基化；Ki = 20 microM）以及可能的其他CYP同工酶（抑制7 - N - 去甲基化；Ki = 58 microM）均有抑制作用。奋乃静对咖啡因氧化的抑制效力与左美丙嗪相似。与左美丙嗪相比，硫利达嗪对咖啡因3 - N - 和7 - N - 去甲基化的抑制作用较弱，而氯丙嗪对咖啡因1 - N - 和7 - N - 去甲基化的抑制作用较弱。总之，所得结果表明，所有研究的抗精神病药在大鼠肝脏中均具有广泛的CYP抑制谱。所有研究的抗精神病药均能明显抑制CYP1A2和CYP3A2同工酶，而奋乃静和左美丙嗪能抑制其他CYP同工酶（CYP2B和/或2E1）。对CYP3A2的抑制最为显著（Ki = 20 - 40 microM）。
