Rodopoulos N, Wisén O, Norman A
Department of Clinical Chemistry, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Scand J Clin Lab Invest. 1995 May;55(3):229-42. doi: 10.3109/00365519509089618.
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 < 0.01 vs. controls), whereas the metabolism through the TB + TP pathways increased to 33 (30-47)%, p < 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 < 0.01 vs. controls), whereas N1-demethylation increased 30 (21-46)%, p < 0.01. The major C8-oxidation reaction, the oxidation of 1-methylxanthine, increased in patients (p < 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.
对13例慢性肝病患者和11名健康对照者给予200毫克（1030微摩尔）咖啡因（CA）的口服负荷量。通过跟踪CA及其代谢产物的血浆浓度和尿排泄来测定CA的代谢情况。此外，对6例患者口服[2-¹⁴C] -咖啡因，以确认其通过不同途径的排泄情况。通过高效液相色谱法和毛细管电泳法分离并定量CA及其14种主要代谢产物。患者中CA的中位（四分位间距）半衰期为19（6.3 - 32）小时，对照者为3.8（3.4 - 4.7）小时。患者中半衰期范围较宽表明肝功能障碍程度不同。在对照者中，仅3（2 - 4）%的给予的CA以未代谢形式经尿液排泄，主要降解途径是通过副黄嘌呤（PX）途径，占82（75 - 83）%。可可碱（TB）和茶碱（TP）途径合并（TB + TP）占CA代谢的15（13 - 21）%。尽管患者中未代谢CA的排泄量为6（3 - 8）%，与对照者相似，但通过PX途径的代谢，占62（44 - 65）%，有所下降（与对照者相比，p < 0.01），而通过TB + TP途径的代谢增加至33（30 - 47）%，p < 0.01。在对照者中，排泄的代谢产物中分别观察到N3 -、N7 -和N1 -去甲基化的比例为86（83 - 89）%、66（62 - 70）%和13（9 - 18）%。在患者中，N3 -去甲基化比例为71（66 - 77）%，N7 -去甲基化比例为54（48 - 59）%，均下降（与对照者相比，p < 0.01），而N1 -去甲基化增加30（21 - 46）%，p < 0.01。主要的C8 -氧化反应，即1 -甲基黄嘌呤的氧化，在患者中增加（p < 0.01）。我们得出结论，慢性肝病中CA代谢减慢是由于影响通过PX途径进行生物转化的N3 -和N7 -去甲基化减少所致。
