Caffeine clearance and biotransformation in patients with chronic liver disease

Abstract

1. The clearance and biotransformation of caffeine (1,3,7-trimethylxanthine) were investigated in eight healthy control subjects and 16 patients with cirrhosis, by measuring serial serum caffeine concentrations and recoveries of methylxanthine metabolites in urine for 48 h after a 400 mg oral caffeine load. 2. In the control group, the mean (+/- SD) serum caffeine clearance was 1.3 +/- 0.4 ml min-1 kg-1 and a mean of 56.4 +/- 16.5% of the administered caffeine was recovered from the urine over 48 h as methyluric acids and methylxanthines. The majority of the metabolites were excreted in the first 24 h period and only 2.0 +/- 1.4% of the administered caffeine was excreted unchanged. 3. Patients with compensated cirrhosis (n = 10) metabolized caffeine similarly to the control subjects. Thus the mean serum caffeine clearance was 1.4 +/- 1.2 ml min-1 kg-1 and a mean of 57.2 +/- 11.7% of the administered caffeine was recovered from the urine over 48 h. The majority of the metabolites were excreted in the first 24 h; the pattern of metabolic excretion was unaltered and only 2.2 +/- 0.9% of the administered caffeine was excreted unchanged. 4. In the patients with decompensated cirrhosis (n = 6), significant changes were observed in caffeine metabolism. The mean serum caffeine clearance (0.4 +/- 0.2 ml min-1 kg-1) was significantly impaired compared with controls (P less than 0.01) and a significant delay was observed in metabolite excretion in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of caffeine and its dimethylxanthine metabolites in patients with chronic liver disease.

“…In healthy volunteers only 1-3% of an administered caffeine load is excreted unchanged in the urine (Arnaud & Welsch, 1981;Callahan et al, 1982;Scott et al, 1988) and its biotransformation is unchanged in patients with chronic liver disease (Scott et al, 1988). Caffeine is extensively metabolised by the hepatic cytochrome P-450 drug metabolising system; thus, for all practical purposes the total clearance of caffeine, calculated from pharmacokinetic variables, is equivalent to its hepatic clearance.…”

Comparison of Hepatic Drug‐Oxidizing Activity after Simultaneous Administration of Two Probe Drugs, Caffeine and Trimethadione, to Human Subjects

“…1986;Joers & Richter 1987;Carbo et al 1989) and liver disorders (Jost & Richter 1987;Bianchettic ef al. 1988;Marchesini et al 1988;Scott et al 1988;Holstege et al 1989;Cheng et al 1990) can moderately affect the metabolic clearance of caffeine. However, few reports concerning these trimethadione factors in humans have been published (Tanaka et al 1987a(Tanaka et al , b & 1991.…”

“…Like antipyrine, both caffeine, (Jost et al 1987;Bianchettic et al 1988;Marchesini et al 1988;Scott et al 1988;Holstege et al 1989;Cheng et al 1990) and trimethadione (Tanaka et al 1987a are currently used as probes to estimate hepatic drug-oxidizing capacity in patients with liver disease. Caffeine and trimethadione are rapidly absorbed from the gastrointestinal tract when given orally, and are exclusively N-demethylated to three metabolites, namely theophylline, theobromine and paraxanthine, and to dimethadione, respectively, by a cytochrome P450 (P450)-dependent monoxygenase in the liver.…”

Funktionsdiagnostik vor Leberresektion - teuer und ohne klinische Relevanz?

“…Schließlich wurde bei Kindern eine größere Sensitivität des Tests bei akutem Leberversagen im Vergleich mit den King's College Kriterien propagiert [36]. Originalarbeiten und Übersichten in allen Studien belegt werden [50,55]. Auch beeinflusst Rauchen die Koffein-Clearance erheblich [50].…”

“…Eine Injektion von 0,5 mg / kg KG sättigt das entsprechende enzymatische System ab, sodass anschließend die Geschwindigkeit der Verstoffwechselung allein in Abhängigkeit von der Menge an und Geschwindigkeit des verstoffwechselnden Enzyms bestimmt werden kann. Diese Geschwindigkeit der Verstoffwechselung ist allerdings altersabhängig [54,55].…”