Nicotine metabolism in isolated perfused lung and liver of phenobarbital- and benzoflavone-treated rats

Abstract

The kinetics of nicotine elimination was investigated in isolated perfused lung and liver of phenobarbital (PB)- and 5,6-benzoflavone (BF)-pretreated rats. The estimated kinetic parameters demonstrated a high nicotine elimination rate in rat lung approaching the capacity of liver when both organs were in an uninduced state. The concentration-time profiles of cotinine as the main metabolite were almost identical for isolated lung and liver. In both organs the cotinine plasma concentrations reached a plateau level after 60 min of perfusion. Pretreatment of rats with 5,6-benzoflavone did not affect the rate of nicotine elimination and cotinine formation either in the lung or in the liver. Phenobarbital treatment, however, induced nicotine clearance in lung approximately 2-fold. This effect is quantitatively lower than the PB-related 8-fold induction of hepatic nicotine elimination observed in a previous study. The present results also indicate that the turnover of cotinine is markedly enhanced after PB induction. The elimination half-lives and clearance values for cotinine as the substrate were approximately 10-fold increased in rat liver after PB pretreatment. Thus, an important contribution of extrahepatic tissues to nicotine metabolism in rats has to be assumed. Moreover, since cotinine elimination is significantly increased after PB induction it is questionable whether cotinine plasma concentrations can further be used as suitable parameter for nicotine consumption.

Increased cotinine elimination and cotinine-N-oxide formation by phenobarbital induction in rat and mouse

“…As shown previously, nicotine elimination and formation of the main metabolite, cot±nine, in un- treated isolated rat lungs are as effective as in isolated livers [11]. The capacity to metabolize cot±n-ine, however, is low in isolated rat lungs, demonstrated by the slow elimination when cot±nine is used as the substrate as well as by the almost constant concentrations during late perfusion when cot±nine is the metabolite of nicotine ( Fig.…”

“…In contrast to the parent compound, the metabolite of primary C-oxidation, cotinine, is eliminated slowly from the plasma [2,6,21]. Usually, the plasma concentrations of cotinine in smokers exceed those of nicotine, and it has been recommended that the plasma levels of cotinine should be used as a measure of nicotine consumption or abstinence [2, 12, 19, 211. In previous studies in rats we obtained evidence that PB induction markedly enhanced nicotine elimination and also the turnover of cotinine [11].…”

“…In PB-treated rats receiving nicotine either intravenously or orally, the elimination of the metabolite cot±nine is increased four to seven times compared with control conditions [11] (Table 1). It remains unclear whether this effect is due to PB induction of hepatic metabolism only or also of extrahepatic secondary metabolism of nicotine.…”

“…Small silastic tubing was implanted chronically into the vena cava to enable blood sampling in conscious animals (details are described in reference [11]). In most cases PB or saline treatment was started on the first day after surgery.…”

“…It was also shown that in this species the extrahepatic metabolism of nicotine contributes significantly to total clearance of nicotine [10,11].…”