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Reduced Blood Clearance and Increased Urinary Excretion of N-Nitrosodimethylamine in Patas Monkeys Exposed to Ethanol or Isopropyl Alcohol¹

Laboratory of Comparative Carcinogenesis, National Cancer Institute [L. M. A., J. M. R.], and DynCorp/Program Resources, Inc. [E. B. S., S. K.], Frederick Cancer Research and Development Center, Frederick, Maryland 21702; Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19140 [G. W. H., R. K.]; Department of Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406 [E. S. B., C. T. G.]; SEMA, Inc., Rockville, Maryland 20850 [T. J. M., J. M. P.]; and Fels Research Institute, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 [P. N. M.]

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.

¹ This study was supported in part by USPHS Grant CA-43342 awarded by the National Cancer Institute, Department of Health and Human Services; Grant SIG-6A from the American Cancer Society; and Contract NO1-CP-71079 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Frederick Cancer Research and Development Center, Building 538, Ft. Detrick, Frederick, MD 21702.

Received 10/24/91. Accepted 1/ 3/92.

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