Raaska Kari, Raitasuo Virpi, Laitila Jouko, Neuvonen Pertti J
Department of Clinical Pharmacology, University of Helsinki, FIN-00290 Helsinki, Finland.
Basic Clin Pharmacol Toxicol. 2004 Jan;94(1):13-8.
Clozapine and caffeine are metabolised mainly by the cytochrome P4501A2 (CYP1A2) enzyme. Studies suggest that caffeine in coffee inhibits clozapine metabolism and increases serum clozapine concentrations. Our objective was to study whether coffee in the amounts usually consumed has an effect on steady-state serum clozapine concentrations. A randomised placebo-controlled cross-over design with two phases was used. Twelve hospitalised clozapine-using patients volunteered in the study where, after one-week run-in period, either caffeine-containing or decaffeinated instant coffee was available ad libitum for seven days. Serum concentrations of clozapine, N-desmethylclozapine, clozapine-N-oxide, caffeine, paraxanthine and C-reactive protein were measured after run-in period and on days 4 and 8 of the following study phases. Two patients were excluded from the statistical analysis because of non-compliance based on serum caffeine and paraxanthine determinations. In six fully compliant patients caffeine-containing coffee increased the mean serum trough concentration of clozapine by 26% (non-significant (NS), 95% CI -3% to +54%, P=0.07), N-desmethylclozapine by 6% (95% CI 1% to 12%, P=0.03), and clozapine-N-oxide by 7% (NS, 95% CI -6% to +20%, P=0.22). The ratio of N-desmethylclozapine/clozapine decreased by 13% (NS, 95% CI -1% to +27%, P=0.06) and that of clozapine-N-oxide/clozapine by 7% (NS, 95% CI -5% to +17%, P=0.19). In the analysis of combined data (including day 4 data of the four patients compliant up to that point) serum trough concentration of clozapine was 20% (95% CI 3% to 37% to P=0.03) higher, and that of N-desmethylclozapine 7% (95% CI 2% to 13%, P=0.02) higher during the caffeine phase than during the decaffeinated phase. We conclude that the effect of instant coffee drinking on serum clozapine concentrations is of minor clinical relevance in most of the patients, but some individuals may be more sensitive to this interaction due e.g. to genetic factors. The increase in serum clozapine concentration was most likely due to the inhibition of the CYP1A2 enzyme by caffeine.
氯氮平和咖啡因主要通过细胞色素P4501A2（CYP1A2）酶进行代谢。研究表明，咖啡中的咖啡因会抑制氯氮平的代谢，并增加血清氯氮平浓度。我们的目的是研究通常饮用的咖啡量是否会对氯氮平的稳态血清浓度产生影响。采用了一个分为两个阶段的随机安慰剂对照交叉设计。12名住院使用氯氮平的患者自愿参与该研究，在为期一周的导入期后，含咖啡因或不含咖啡因的速溶咖啡可随意饮用7天。在导入期结束后以及接下来研究阶段的第4天和第8天，测量氯氮平、N-去甲基氯氮平、氯氮平-N-氧化物、咖啡因、副黄嘌呤和C反应蛋白的血清浓度。两名患者因根据血清咖啡因和副黄嘌呤测定结果显示未依从研究而被排除在统计分析之外。在6名完全依从的患者中，含咖啡因的咖啡使氯氮平的平均血清谷浓度升高了26%（无统计学意义（NS），95%置信区间为-3%至+54%，P = 0.07），N-去甲基氯氮平升高了6%（95%置信区间为1%至12%，P = 0.03），氯氮平-N-氧化物升高了7%（无统计学意义，95%置信区间为-6%至+20%，P = 0.22）。N-去甲基氯氮平/氯氮平的比值下降了13%（无统计学意义，95%置信区间为-1%至+27%，P = 0.06），氯氮平-N-氧化物/氯氮平的比值下降了7%（无统计学意义，95%置信区间为-5%至+17%，P = 0.19）。在合并数据的分析中（包括截至当时4名依从患者第4天的数据），咖啡因阶段氯氮平的血清谷浓度比不含咖啡因阶段高20%（95%置信区间为3%至37%至P = 0.03），N-去甲基氯氮平高7%（95%置信区间为2%至13%，P = 0.02）。我们得出结论，饮用速溶咖啡对血清氯氮平浓度的影响在大多数患者中临床相关性较小，但一些个体可能由于例如遗传因素等对这种相互作用更为敏感。血清氯氮平浓度的升高很可能是由于咖啡因对CYP1A2酶的抑制作用。
