Caffeine metabolism in liver cirrhosis

Abstract

Caffeine is metabolized primarily by CYP1A2. Several methods have been developed for the in vivo assessment of CYP1A2 activity using caffeine as a probe drug (2). These methods include the determination of caffeine clearance as well as the estimation of caffeine metabolic ratios in urine, saliva and plasma samples and they have been proposed to assess the in vivo activity of hepatic enzymes in healthy subjects and in patients with liver disease (3-6). Caffeine metabolites in urine are 1-methyluric acid (1U), 5-acetylamino-6-formylamino-3- methyluracil (AFMU), 1-methylxanthine (1X), 1,7-dimethyluric acid (17U) and 1,7-dimethylxanthine (17X). The activity of CYP1A2, xanthine oxidase (XO) and CYP2A6 can be estimated from the urinary metabolic ratios (AFMU+1U+1X)/17U, 1U/1X and 17U/17X, respectively. The purpose of the present study was to use caffeine in vivo as a probe drug in patients with liver disease in order to assess the effects of the severity of the disease on the enzymatic activity of CYP1A2, CYP2A6 and XO. The present study included 38 healthy volunteers and patients with compensated (n=33) and decompensated (n=19) liver cirrhosis. The subjects were requested to avoid consumption of any food and beverages containing caffeine, methylxanthines, alcohol and medication for at least 24 hours before they were administered a capsule containing 200 mg caffeine. A spot urine sample was collected 6 hours later. Samples were analyzed by reversed-phase HPLC. The five metabolites and the internal standard (4-acetamidophenol) were extracted with liquid/liquid extraction using chloroformisopropanol (85:15, v/v). The accuracy of the method ranged between 90.2% and 110.4%. The intraday (n=5) and interday (n=5) precision (CV%) were <9.83% and <12.46%, respectively. CYP1A2 index was significantly decreased in patients with compensated (median 2,84, p=0.004) and decompensated (median 2.52, p<0.001) cirrhosis as compared to healthy subjects (median 3.73). However, there was no statistically significant difference in CYP2A6 index between patients with compensated (median 1.07, p>0.05) and decompensated (median 1.19, p>0.05) cirrhosis as compared to healthy subjects (median 1.67). Similarly, there was no statistically significant difference in XO index between patients with compensated (median 1.30, p>0.05) and decompensated (median 1.28, p>0.05) cirrhosis as compared to healthy subjects (median 1.16). In conclusion, CYP1A2 activity is reduced in patients with liver cirrhosis. (AFMU+1U+1X)/17U calculated from a spot urine sample may be used as a simple, non-invasive method for the in vivo assessment of CYP1A2 activity in patients with liver cirrhosis.