Phenacetin metabolism: Effect of hydrocarbons and cigarette smoking

The effects of cigarette smoking on phenacetin metabolism in the rat and in man have been investigated. Exposure of rats to cigarette smoke or pretreatment with the polycyclic hydrocarbon, 3,4-benzpyrene (benzo[a]pyrene), resulted in a more rapid disappearance of phenacetin in vivo. Additional studies demonstrated that hydrocarbon and smoking pretreatment of rats enhanced the 0-dealkylation of phenacetin to N-acetyl-p-aminophenol (APAP) by the intestinal mucosa. Cigarette smoking also increased the metabolism of phenacetin in man. The plasma concentration of phenacetin in cigarette smokers was lower than that in nonsmokers, whereas the ratio of the concentration of APAP to that of phenacetin was increased severalfold in the smokers. No difference in plasma half-life of elimination of phenacetin or in the amount of APAP excreted was found between smokers and nonsmokers. The lower blood levels of phenacetin in cigarette smokers could be the result of increased intestinal metabolism of the drug and/or first-pass metabolism in the liver.