Pieniaszek H J, Davidson A F, McEntegart C M, Quon C Y, Sampliner R E, Mayersohn M
Drug Metabolism and Pharmacokinetics Section, DuPont Merck Pharmaceutical Company, Stine-Haskell Research Center, Newark, Delaware.
Biopharm Drug Dispos. 1994 Apr;15(3):243-52. doi: 10.1002/bdd.2510150306.
The pharmacokinetics of moricizine and two of its metabolites, moricizine sulfoxide and phenothiazine-2-carbamic acid ethyl ester sulfoxide, were studied in healthy control subjects and in patients with chronic liver disease (cirrhosis). Moricizine disposition was significantly altered by hepatic cirrhosis. Compared to healthy subjects, the hepatic disease patients had an increased Cmax (59%), an increased t1/2 (141%), and a reduced plasma clearance (71%). Additionally, small but statistically significant increases were observed for tmax and the fraction of moricizine not bound to plasma proteins in patients with hepatic disease. The elimination of both moricizine metabolites was also altered by hepatic dysfunction as indicated by significantly prolonged terminal half-lives. Furthermore, there was a reduction in the conversion of moricizine to moricizine sulfoxide. Both hepatic blood flow and hepatic metabolizing capacity were assessed in all subjects and patients by administration of indocyanine green and antipyrine, respectively. Indocyanine green and antipyrine plasma clearances were decreased by 38 and 51%, respectively, indicating that both functions were diminished by hepatic cirrhosis. We conclude that the moricizine dose required for arrhythmia patients with hepatic disease should be lower, and perhaps, the dosing frequency should be less than in patients with normal liver function.
在健康对照受试者和慢性肝病（肝硬化）患者中研究了莫雷西嗪及其两种代谢产物（亚砜莫雷西嗪和吩噻嗪-2-氨基甲酸乙酯亚砜）的药代动力学。肝硬化显著改变了莫雷西嗪的处置。与健康受试者相比，肝病患者的Cmax升高（59%），t1/2延长（141%），血浆清除率降低（71%）。此外，肝病患者的tmax和未与血浆蛋白结合的莫雷西嗪分数有小幅但具有统计学意义的增加。肝功能障碍也改变了两种莫雷西嗪代谢产物的消除，表现为终末半衰期显著延长。此外，莫雷西嗪向亚砜莫雷西嗪的转化减少。分别通过给予吲哚菁绿和安替比林对所有受试者和患者的肝血流量和肝脏代谢能力进行了评估。吲哚菁绿和安替比林的血浆清除率分别降低了38%和51%，表明肝硬化使这两种功能均减弱。我们得出结论，肝病心律失常患者所需的莫雷西嗪剂量应更低，或许给药频率应低于肝功能正常的患者。
