Suppression of in vivo clearance of N-nitrosodimethylamine in mice by cotreatment with ethanol.

Oral cotreatment of mice with ethanol results in increased tumors in extrahepatic organs caused by some nitrosamines. This action, attributed in part to inhibition of hepatic first-pass carcinogen metabolism by ethanol, has possible relevance to the enhancing effect of alcoholic beverage consumption on human cancer risk. In this study, the effects of ethanol on clearance of N-nitrosodimethylamine (NDMA) were quantified in Swiss female and strain A male mice. In Swiss mice, a 1.6 g/kg ig ethanol dose preceding 1 or 5 mg/kg iv NDMA resulted in 20- to 30-fold increases in area-under-the-blood-concentration-vs.-time curves, mean residence times, and clearance half-times, and similar decreases in clearance. For a 0.5 mg/kg ig NDMA dose, the pharmacokinetic parameters were altered 30-fold and 450-fold by simultaneous ethanol doses of 0.08 and 0.8 g/kg, respectively. With 5 mg NDMA/kg ig, 0.4, 0.8, and 1.6 g/kg ethanol resulted in 6-, 10-, and 20-fold changes in clearance parameters. Comparison of the data with results obtained previously with patas monkeys indicated comparable effects of ethanol on tissue exposure to NDMA in the two species, confirming potential human applicability. In experiments with strain A mice, NDMA concentrations were also monitored in lung and liver. NDMA amounts in lung paralleled those in blood, and were more than sufficient to account for the previously reported increases in DNA adducts and tumors in lungs of similarly treated strain A mice.

Reduced blood clearance and increased urinary excretion of N-nitrosodimethylamine in patas monkeys exposed to ethanol or isopropyl alcohol.

Low concentrations of N-nitrosodimethylamine are metabolized in rodent and human liver by cytochrome P450IIE1, an activity competitively inhibitable by ethanol. In rodents coadministration of ethanol with N-nitrosodimethylamine results in increased tumorigenicity in extrahepatic organs, probably as a result of reduced hepatic clearance. To test this concept in a primate, the effects of ethanol cotreatment on the pharmacokinetics of N-nitrosodimethylamine were measured in male patas monkeys. Ethanol, 1.2 g/kg given p.o. before i.v. N-nitrosodimethylamine (1 mg/kg) or concurrently with an intragastric dose resulted in a 10-50-fold increase in the area under the blood concentration versus time curves and a 4-13-fold increase in mean residence times for N-nitrosodimethylamine. Isopropyl alcohol, 3.2 g/kg 24 h before N-nitrosodimethylamine, also increased these parameters 7-10-fold; this effect was associated with persistence of isopropyl alcohol and its metabolic product acetone, both IIE1 inhibitors, in the blood. While no N-nitrosodimethylamine was detected in expired air, trace amounts were found in urine. Ethanol and isopropyl alcohol pretreatment increased the maximum urinary N-nitrosodimethylamine concentration 15-50-fold and the percentage of the dose excreted in the urine by 100-800-fold. Thus ethanol and isopropyl alcohol greatly increase systemic exposure of extrahepatic organs to N-nitrosodimethylamine in a primate.

Estimation of the fraction of the dose of N-nitrosodimethylamine metabolized to methylamine in rats.

Despite many years of research on the metabolism of N-nitrosodimethylamine (NDMA) in rats, the significance of enzymatic denitrosation as a pathway remains unclear. To assess the role of this pathway of metabolism in rats, animals were administered NDMA by intravenous infusion at two infusion rates until steady state was achieved and the concentrations of NDMA (Css,NDMA) and methylamine (MA) (Css,MA), a product of the enzymatic denitrosation pathway, were determined in plasma. The clearance of NDMA (ClNDMA) from plasma was determined by dividing the infusion rate by Css,MA. The plasma clearance of MA (ClNDMA) was determined in a separate experiment. The fraction of the dose of NDMA metabolized by enzymatic denitrosation (fm) was calculated using the equation fm = (Css,MA*ClMA)/(Css,NDMA*ClNDMA). By this method it was estimated that 29% of the dose of NDMA was metabolized via the enzymatic denitrosation pathway. Thus enzymatic denitrosation is an important pathway in the metabolism of NDMA in rats.