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.
Anderson
L M
LM
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick, Maryland.
Koseniauskas
R
R
Burak
E S
ES
Moskal
T J
TJ
Gombar
C T
CT
Phillips
J M
JM
Sansone
E B
EB
Keimig
S
S
Magee
P N
PN
Rice
J M
JM
D000433:1-Propanol / Q000097:blood / Q000494:pharmacology*; D000096:Acetone / Q000097:blood; D000818:Animals; D004128:Dimethylnitrosamine / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004901:Erythrocebus patas; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D008297:Male; D011292:Premedication
D000096:Acetone; D000431:Ethanol; D000433:1-Propanol; D004128:Dimethylnitrosamine