Caraco Y, Sheller J, Wood A J
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
J Pharmacol Exp Ther. 1997 Apr;281(1):330-6.
Our objective was to examine the effect of rifampin on codeine's pharmacodynamics and pharmacokinetics in extensive (EMs) and poor (PMs) metabolizers of debrisoquin. Fifteen healthy, nonsmoking males, 9 EMs and 6 PMs of debrisoquin, received codeine (120 mg) before and after rifampin (600 mg/d) for 3 weeks. The effects of codeine on respiration, pupil diameter and psychomotor performance were measured before codeine administration and during each study day. The pharmacokinetics of codeine were determined from the respective plasma and urine concentrations. Before the administration of rifampin, the pharmacodynamic effects of codeine were more prominent in the EMs (P < .01). Rifampin significantly enhanced codeine oral clearance by increasing its metabolic clearances through N-demethylation and glucuronidation in both phenotypes, but its O-demethylation was induced only in EMs. Relative to base-line values, codeine N-demethylation was induced to a greater extent, resulting in a marked reduction in the plasma concentrations of codeine and codeine metabolites and elevated plasma concentrations of norcodeine, norcodeine-glucuronide, and normorphine. The reduction in morphine plasma concentration was associated in the EMs with a significant attenuation of codeine's respiratory and psychomotor effects, whereas its miotic effect was unaltered. In PMs, codeine's respiratory and psychomotor effects were unaltered by rifampin, but its pupillary effect was reduced. Codeine O-demethylation to produce morphine can be significantly induced by rifampin, but this induction is phenotypically determined. However, because (relative to base-line values) rifampin enhanced codeine N-demethylation more than codeine O-demethylation, morphine plasma concentrations were reduced-and hence codeine's pharmacodynamic effects were attenuated-in EMs of debrisoquin.
我们的目的是研究利福平对异喹胍广泛代谢者（EMs）和代谢不良者（PMs）中可待因的药效学和药代动力学的影响。15名健康、不吸烟的男性，其中9名是异喹胍的EMs，6名是PMs，在服用利福平（600mg/d）3周前后分别服用可待因（120mg）。在服用可待因前以及每个研究日期间，测量可待因对呼吸、瞳孔直径和精神运动表现的影响。根据各自的血浆和尿液浓度确定可待因的药代动力学。在服用利福平之前，可待因的药效学作用在EMs中更为显著（P<0.01）。利福平通过增加两种表型中可待因经N-去甲基化和葡萄糖醛酸化的代谢清除率，显著提高了可待因的口服清除率，但仅在EMs中诱导了其O-去甲基化。相对于基线值，可待因的N-去甲基化诱导程度更大，导致可待因及其代谢物的血浆浓度显著降低，而去甲可待因、去甲可待因-葡萄糖醛酸和去甲吗啡的血浆浓度升高。在EMs中，吗啡血浆浓度的降低与可待因呼吸和精神运动作用的显著减弱相关，而其缩瞳作用未改变。在PMs中，利福平未改变可待因的呼吸和精神运动作用，但其瞳孔作用减弱。利福平可显著诱导可待因O-去甲基化生成吗啡，但这种诱导作用由表型决定。然而，因为（相对于基线值）利福平增强可待因N-去甲基化的程度大于可待因O-去甲基化，所以在异喹胍的EMs中吗啡血浆浓度降低，因此可待因的药效学作用减弱。
