Denaro C P, Wilson M, Jacob P, Benowitz N L
Division of Clinical Pharmacology and Experimental Therapeutics, San Francisco General Hospital Medical Center, CA 94110, USA.
Clin Pharmacol Ther. 1996 Jun;59(6):624-35. doi: 10.1016/S0009-9236(96)90002-8.
A number of caffeine metabolite ratios (CMRs) have been proposed to measure CYP1A2 activity in vivo. The effect of liver disease on these ratios is not clear. The objective of this study was to determine the influence of liver disease on caffeine metabolite ratios.
Two studies were performed. First, in healthy control subjects and in subjects with cirrhosis, caffeine clearance was measured by intravenous infusion of stable isotope-labeled caffeine while subjects consumed oral caffeine. Second, spot urine samples were collected from control subjects and from subjects with either chronic hepatitis or cirrhosis while they consumed caffeine.
In study 1, caffeine clearance was decreased in subjects with cirrhosis (control mean, 0.14 L/hr/kg; cirrhosis mean, 0.04 L/hr/kg; p = 0.003). CMRs were affected by liver disease (e.g., ratio characterizing paraxanthine demethylation [AAMU + 1X + 1U/17U], control median, 8.3; cirrhosis median, 6.2; p = 0.005). AAMU + 1X + 1U/17U correlated significantly with caffeine clearance in the control group (r2 = 0.68; p = 0.0001) and in subjects with cirrhosis (r2 = 0.41; p = 0.05). In study 2, there was a significant difference between control subjects and subjects with cirrhosis for AAMU + 1X + 1U/17U (median for control subjects, 6.2; median for subjects with cirrhosis, 4.3; p = 0.001) but not between control subjects and patients with chronic hepatitis.
We conclude that AAMU + 1X + 1U/17U is affected by liver disease and reflects the decrease in CYP1A2 activity in subjects with cirrhosis. AAMU + 1X + 1U/17U measured from a spot urine sample reflects caffeine clearance in subjects with cirrhosis and may be useful as a hepatic function test. Despite the large interindividual variation observed, the test can be repeated easily in the same patient and an individual patient's decline in CYP1A2 activity, such as in patients with progressively deteriorating liver function, can be monitored.
已提出多种咖啡因代谢物比率（CMRs）用于在体内测量CYP1A2活性。肝脏疾病对这些比率的影响尚不清楚。本研究的目的是确定肝脏疾病对咖啡因代谢物比率的影响。
进行了两项研究。首先，在健康对照受试者和肝硬化受试者中，通过静脉输注稳定同位素标记的咖啡因同时受试者口服咖啡因来测量咖啡因清除率。其次，在对照受试者以及患有慢性肝炎或肝硬化的受试者饮用咖啡因时收集即时尿样。
在研究1中，肝硬化受试者的咖啡因清除率降低（对照组均值，0.14L/（小时·千克）；肝硬化组均值，0.04L/（小时·千克）；p = 0.003）。CMRs受肝脏疾病影响（例如，表征对黄嘌呤去甲基化的比率[AAMU + 1X + 1U/17U]，对照组中位数，8.3；肝硬化组中位数，6.2；p = 0.005）。在对照组中，AAMU + 1X + 1U/17U与咖啡因清除率显著相关（r2 = 0.68；p = 0.0001），在肝硬化受试者中也显著相关（r2 = 0.41；p = 0.05）。在研究2中，对照组与肝硬化受试者在AAMU + 1X + 1U/17U方面存在显著差异（对照组中位数，6.2；肝硬化受试者中位数，4.3；p = 0.001），但对照组与慢性肝炎患者之间无显著差异。
我们得出结论，AAMU + 1X + 1U/17U受肝脏疾病影响，并反映肝硬化受试者中CYP1A2活性的降低。从即时尿样中测得的AAMU + 1X + 1U/（17U）反映肝硬化受试者的咖啡因清除率，可用作肝功能检测。尽管观察到个体间差异较大，但该检测可在同一患者中轻松重复进行，并且可以监测个体患者CYP1A2活性的下降情况，例如在肝功能逐渐恶化的患者中。
