CAFFEINE METABOLISM IN PATIENTS WITH CHRONIC LIVER-DISEASE

An oral load of 200 mg (1030 mu mol) caffeine (CA) was given to 13 pat ients with chronic Liver diseases and to 11 healthy controls. The meta bolism of CA was determined by following plasma concentrations and uri nary excretion of CA and its metabolites. In addition, [2-C-14]-caffei ne was given orally to six patients to confirm the excretion through t he different pathways. CA and its 14 main metabolites were separated a nd quantified by high performance liquid chromatography and capillary electrophoresis. Median (interquartile range) half-lives of CA were 19 (6.3-32) h in the patients and 3.8 (3.4-4.7)h in the controls. The wi de range in the patients indicated varying degrees of liver dysfunctio n. Only 3 (2-4)% of administered CA was excreted unmetabolized in urin e in the controls and the main degradation was through the paraxanthin e (PX) pathway 82 (75-83)%. The combined theobromine (TB) and theophyl line (TP) pathways (TB + TP) accounted for 15 (13-21)% of CA metabolis m. Although the excretion of unmetabolized CA in the patients 6 (3-8)% , was similar to that in the controls, the metabolism through the PX p athway, 62 (44-65)%, decreased (p < 0.01 ys. controls), whereas the me tabolism through the TB + TP pathways increased to 33 (30-47)%, p < 0. 01. In controls, N3-, N7- and N1-demethylations were observed in 86 (8 3-89)%, 66 (62-70)% and 13 (9-18)%, respectively, of excreted metaboli tes. In patients the N3-demethylations, 71 (66-77)%, and N7-demethylat ions, 54 (48-59)%, decreased (p < 0.01 vs. controls), whereas N1-demet hylation increased 30 (21-46)%, p < 0.01. The major C8-oxidation react ion, the oxidation of 1-methylxanthine, increased in patients (p < 0.0 1). We conclude that the slowed metabolism of CA in chronic liver dise ase is due to reduced N3- and N7-demethylations affecting biotransform ation through the PX pathway.