Caffeine metabolism in patients with chronic liver disease
Author: Rodopoulos N; WisÆen O; Norman A
Address: Department of Clinical Chemistry, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Source: Scand J Clin Lab Invest, 1995 May, 55:3, 229-42
An oral load of 200 mg (1030 mumol) caffeine (CA) was given to 13 patients with chronic liver diseases and to 11 healthy controls. The metabolism of CA was determined by following plasma concentrations and urinary excretion of CA and its metabolites. In addition, [2-14C]-caffeine was given orally to six patients to confirm the excretion through the different pathways. CA and its 14 main metabolites were separated and 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 wide range in the patients indicated varying degrees of liver dysfunction. Only 3 (2-4)% of administered CA was excreted unmetabolized in urine in the controls and the main degradation was through the paraxanthine (PX) pathway 82 (75-83)%. The combined theobromine (TB) and theophylline (TP) pathways (TB + TP) accounted for 15 (13-21)% of CA metabolism. Although the excretion of unmetabolized CA in the patients 6 (3-8)%, was similar to that in the controls, the metabolism through the PX pathway, 62 (44-65)%, decreased (p less than 0.01 vs. controls), whereas the metabolism through the TB + TP pathways increased to 33 (30-47)%, p less than 0.01. In controls, N3-, N7- and N1-demethylations were observed in 86 (83-89)%, 66 (62-70)% and 13 (9-18)%, respectively, of excreted metabolites. In patients the N3-demethylations, 71 (66-77)%, and N7-demethylations, 54 (48-59)%, decreased (p less than 0.01 vs. controls), whereas N1-demethylation increased 30 (21-46)%, p less than 0.01. The major C8-oxidation reaction, the oxidation of 1-methylxanthine, increased in patients (p less than 0.01). We conclude that the slowed metabolism of CA in chronic liver disease is due to reduced N3- and N7-demethylations affecting biotransformation through the PX pathway.
Language of Publication: English; Unique Identifier 95365748