Differential Effect of Cigarette Smoking on Antipyrine Oxidation versus Acetaminophen Conjugation

Abstract

The effect of cigarette smoking on drug oxidation and conjugation was studied using antipyrine and acetaminophen as marker compounds. For the antipyrine study, healthy cigarette smokers (n = 30) and nonsmoking controls (n = 53) received a single 1.0-gram intravenous dose of antipyrine. For the acetaminophen study, 14 smokers and 15 nonsmokers received a 650-mg intravenous dose of acetaminophen. The clearance of antipyrine was significantly increased (0.93 vs. 0.60 ml/min/kg, p < 0.0001) and elimination half-life was correspondingly reduced (8.9 vs. 13.0 h, p < 0.0001) in smokers compared to nonsmoking controls. Total recovery of antipyrine and metabolites excreted in urine did not differ between groups, but there was a significantly increased fractional clearance of antipyrine via formation of 4-hydroxyantipyrine and 3-hydroxymethyl metabolites in smokers. Fractional clearance via formation of norantipyrine did not differ significantly between groups. Comparison of acetaminophen kinetics between smokers and nonsmokers indicated no significant differences in elimination half-life, clearance or volume of distribution. Thus, cigarette smoking is more likely to induce drug oxidation rather than drug conjugation. However, not all oxidative pathways are equally influenced; induction effects of smoking are highly substrate selective and pathway specific.

UDP Glucuronosyltransferase (UGT) 1A6 Pharmacogenetics: I. Identification of Polymorphisms in the 5′-Regulatory and Exon 1 Regions, and Association with Human Liver UGT1A6 Gene Expression and Glucuronidation

“…The degree of enhancement of N-acetyl-p-benzoquinone imine formation is similar to that which we observed for acetaminophen glucuronidation (less than 2-fold), but may occur more rapidly since the primary mechanism of induction of CYP2E1 is post-translational (Thummel et al, 2000). In good agreement with the results of the present study, cigarette smoking was previously shown in two different studies (Scavone et al, 1990;Miners and Mackenzie, 1991) to have no effect on acetaminophen conjugation in vivo. In contrast, the results of a third study suggested that heavy smoking (Ͼ40 cigarettes per day) was associated with higher urinary acetaminophen glucuronide excretion (Bock et al, 1987).…”

Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system

“…Results from several in vivo studies suggest that the clearance of acetaminophen (Bock et al, 1994; Bock et al, 1987), oxazepam (Ochs et al, 1981), and codeine (Yue et al, 1989; Yue et al, 1994) is higher in cigarette smokers, although the extent of the difference was small and probably clinically unimportant. In contrast, results of several other studies show no effects of smoking on the clearance by glucuronidation of acetaminophen (Miners et al, 1984; Scavone et al, 1990), diflunisal (Macdonald et al, 1990), and lorazepam (Ochs et al, 1985). …”

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“…Measuring of antipyrine clearance (plasma or saliva) makes it possible to explain interindividual and intra-individual variations drug response variations, which may be genetic 20 , secondary to a pathological situation 21 , a drug interaction 22 or related to exogenous factors, such as diet 23,24 , tobacco 25 , physical activity 26 and exposure to chemical substances 27 .…”