Effects of caffeine on biotransformation and elimination kinetics of acetaminophen in mice

Coadministration of caffeine (CAF) with acetaminophen (ACM) to mice prolonged the blood half-life of ACM, increased moderately the fraction of ACM excreted as the glucuronide conjugate, and decreased slightly the fraction excreted as the sulfate conjugate. CAF exerted more profound effects on fractions of ACM metabolites which are formed as a consequence of biotransformation via cytochrome P-450-dependent pathway(s); urinary excretion of ACM-mercapturate was reduced ca. 44%, ACM-cysteine was reduced ca. 24%, and the methylthio metabolites were reduced ca. 30%. The apparent rate constants (K') for ACM metabolite formation were suppressed markedly by CAF. Following CAF coadministration with ACM, the K' values for the sulfate-, mercapturate-, cysteine-, and methylthio metabolites were decreased approximately 35%, 56%, 42%, and 47%, respectively. It was concluded that the protective action of CAF against ACM-induced hepatic injury in mice is mediated by a decrease in the rate of formation of N-acetyl-p-benzoquinoneimine, the reactive metabolite of ACM.