Orlando Rocco, Padrini Roberto, Perazzi Mauro, De Martin Sara, Piccoli Pierpaolo, Palatini Pietro
Department of Pharmacology and Anesthesiology, University of Padua, Italy.
Clin Pharmacol Ther. 2006 May;79(5):489-99. doi: 10.1016/j.clpt.2006.01.012.
In vivo inhibition of cytochrome P450 (CYP) 1A2 by fluvoxamine causes a reduction in the clearance of the high-extraction drug lidocaine, which decreases in proportion to the degree of liver dysfunction. The objectives of this study were (1) to evaluate the effect of liver cirrhosis on the inhibition by fluvoxamine of the metabolic disposition of theophylline, a CYP1A2 substrate with a low-extraction ratio, to assess whether decreased sensitivity to CYP1A2 inhibition in liver disease is a general characteristic of CYP1A2 substrates, regardless of their pharmacokinetic properties, and (2) to investigate the mechanism(s) underlying the effect of liver dysfunction on CYP1A2 inhibition.
The study was carried out in 10 healthy volunteers and 20 patients with cirrhosis, 10 with mild liver dysfunction (Child class A) and 10 with severe liver dysfunction (Child class C), according to a randomized, double-blind, 2-phase, crossover design. In one phase all participants received placebo for 7 days; in the other phase they received one 50-mg fluvoxamine dose for 2 days and two 50-mg fluvoxamine doses, 12 hours apart, in the next 5 days. On day 6, 4 mg/kg of theophylline was administered orally 1 hour after the morning fluvoxamine dose. Concentrations of theophylline and its metabolites, 3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid, were then measured in plasma and urine up to 48 hours.
Fluvoxamine-induced inhibition of theophylline clearance decreased from 62% in healthy subjects to 52% and 12% in patients with mild cirrhosis and those with severe cirrhosis, respectively. CYP1A2-mediated formations of 3-methylxanthine and 1-methyluric acid were almost totally inhibited in control subjects, whereas they were only reduced by one third in patients with Child class C cirrhosis. Inhibition of 1,3-dimethyluric acid formation, which is catalyzed by CYP1A2 and CYP2E1, progressively decreased from 58% in healthy subjects to 43% and 7% in patients with mild cirrhosis and those with severe cirrhosis, respectively.
The effect of liver dysfunction on the inhibition of CYP1A2-mediated drug elimination is a general phenomenon, independent of the pharmacokinetic characteristics of the CYP1A2 substrate. Therefore, for any drug metabolized by CYP1A2, the clinical consequences of enzyme inhibition are expected to become less and less important as liver function worsens. Two mechanisms, as follows in order of importance, are responsible for the effect of liver dysfunction: (1) decreased sensitivity to fluvoxamine of CYP1A2-mediated biotransformations in the cirrhotic liver, probably resulting from reduced uptake of the inhibitory drug, and (2) reduced hepatic expression of CYP1A2, which makes its contribution to overall drug elimination less important.
氟伏沙明在体内对细胞色素P450（CYP）1A2的抑制作用会导致高摄取药物利多卡因的清除率降低，且清除率降低程度与肝功能障碍程度成比例。本研究的目的是：（1）评估肝硬化对氟伏沙明抑制茶碱（一种低摄取率的CYP1A2底物）代谢处置的影响，以评估肝病中对CYP1A2抑制的敏感性降低是否是CYP1A2底物的普遍特征，而不论其药代动力学特性如何；（2）研究肝功能障碍对CYP1A2抑制作用的潜在机制。
本研究按照随机、双盲、两阶段、交叉设计，在10名健康志愿者和20名肝硬化患者中进行，其中10名患者为轻度肝功能障碍（Child A级），10名患者为重度肝功能障碍（Child C级）。在一个阶段，所有参与者接受7天的安慰剂治疗；在另一个阶段，他们接受1次50mg氟伏沙明剂量治疗2天，并在接下来的5天内相隔12小时接受2次50mg氟伏沙明剂量治疗。在第6天，在早晨服用氟伏沙明剂量1小时后口服4mg/kg茶碱。然后在长达48小时内测定血浆和尿液中茶碱及其代谢产物3-甲基黄嘌呤、1-甲基尿酸和1,3-二甲基尿酸的浓度。
氟伏沙明引起的茶碱清除率抑制率从健康受试者的62%分别降至轻度肝硬化患者的52%和重度肝硬化患者的12%。在对照受试者中，CYP1A2介导的3-甲基黄嘌呤和1-甲基尿酸的形成几乎完全受到抑制，而在Child C级肝硬化患者中仅降低了三分之一。由CYP1A2和CYP2E1催化的1,3-二甲基尿酸形成的抑制率从健康受试者的58%分别逐渐降至轻度肝硬化患者的43%和重度肝硬化患者的7%。
肝功能障碍对CYP1A2介导的药物消除抑制作用是一种普遍现象，与CYP1A2底物的药代动力学特征无关。因此，对于任何由CYP1A2代谢的药物，随着肝功能恶化，酶抑制的临床后果预计会变得越来越不重要。肝功能障碍产生这种影响的机制有两个，按重要性排序如下：（1）肝硬化肝脏中CYP1A2介导的生物转化对氟伏沙明的敏感性降低，可能是由于抑制性药物的摄取减少；（2）CYP1A2的肝脏表达降低，这使得其对整体药物消除的贡献变得不那么重要。
