Inhibition of caffeine elimination by short-term ethanol administration

Short-term ethanol ingestion has been shown to inhibit the metabolism of a number of drugs metabolized by cytochrome P-450 in both man and laboratory animals. However, the effects of short-term ethanol administration on the metabolism of cytochrome P-448-dependent drugs in man is unknown. Caffeine is a commonly used drug that is metabolized predominantly by a component of the hepatic microsomal mixed-function oxidase complex, known as cytochrome P-448. Therefore the elimination of caffeine given orally was studied in normal volunteers after receiving either orange juice or 0.8 gm/kg ethanol as a 25% solution in orange juice. Short-term administration of ethanol resulted in a significant decrease in the plasma clearance of caffeine from 96.6 +/- 13.4 ml/min to 60.7 +/- 10.5 (mean +/- S.E., p less than 0.05). There was also a corresponding significant increase in the elimination half-life of caffeine from 4.03 +/- 0.52 hr to 6.04 + 0.73 (mean + S.E., p less than 0.01). To determine whether the decrease in caffeine elimination was due to an inhibition of caffeine metabolism by ethanol or to an effect on caffeine absorption, caffeine disposition was studied in four healthy, mongrel dogs after intravenous administration. Each animal served as its own control. Caffeine clearance decreased significantly from a baseline value of 19.6 +/- 1.5 ml/min to 8.0 +/- 1.5 (mean +/- S.E., p less than 0.05) after administration of 3.0 gm/kg ethanol given orally 1 hr before intravenous caffeine injection. These results imply that short-term administration of ethanol inhibits the metabolism of caffeine, a predominantly cytochrome P-448-dependent substrate, in both man and dogs.