Caffeine metabolism before and after liver transplantation

Aim: To study drug metabolism in patients before and after liver transplant ation using caffeine as a probe drug. Forty-five patients undergoing liver transplantation for various liver diseases and who had well documented doss iers were selected for the study. Before the liver transplantation and I mo nth, I year, and 6 years after liver transplantation, they were given 200 m g of caffeine by the oral route in the morning after voiding their bladder. Twenty-four-hour urine samples were collected and caffeine and,metabolites were determined by HPLC: 1-methylurate (1U), 1-methylxanthine (1X), 1.7-di methylurate (17X), 1.7-dimethylxanthine (17X), 7-methylxanthine (7X), 3-met hylxanthine (3X), 1.3-dimethylurate (13U), 3.7-dimethylxanthine (37X), 1.3- dimethylxanthine (13X), 1.3.7-trimethylxanthine = caffeine (137X). Indices of enzyme activities were calculated from the following urinary elimination ratios: (AFMU+1U+1X)/17U or CYP1A2,17U/17X for CYP2A6, 1U/1X for xanthine oxidase (XO), AFMU/(AFMU+ 1U+1X) for N-acetyltransferase (NAT-2). Results: Compared with results obtained in a group of 70 healthy subjects, caffeine metabolism before liver transplantation was deeply depressed with a decreas ed elimination rate in the case of all metabolites and a decreased CYP1A2 a ctivity. Caffeine metabolism began to return to the control values one mont h after transplantation. One year and 6 years after liver transplantation, quantitatively, the metabolism of caffeine was stable and not different fro m control, but with qualitative modifications. CYP1A2 activity was decrease d with reduced urinary elimination rates of 1X and 17X. XO and CYP2A6 activ ities and 1U and 17U urinary elimination rates were increased. Immunosuppre ssive treatment was possibly responsible for the metabolic pathway changes. Almost the same modifications were observed in 9 patients after bone marro w transplantation who had been treated with the same immumosuppressive drug s, cyclosporine and azathioprine. During severe rejection phases in 6 of th e liver transplant patients, caffeine metabolism was progressively decrease d when the usual liver function tests showed moderate but uniform changes. Conclusion: Despite an apparent normal drug-metabolic function, immunosuppr essive treatment induces stable variations in drug-metabolic pathways after liver transplantation which can be detected from the changes in caffeine m etabolism.