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.
Burak
E S
ES
Department of Chemistry, Temple University, Philadelphia, PA.
Harrington
G W
GW
Koseniauskas
R
R
Gombar
C T
CT
D000818:Animals; D004128:Dimethylnitrosamine / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008433:Mathematics; D008744:Methylamines / Q000097:blood / Q000378:metabolism; D015538:Nitrosation; D051381:Rats; D011919:Rats, Inbred Strains
D008744:Methylamines; C027451:methylamine; D004128:Dimethylnitrosamine