Toxicokinetics ofN-nitrosodimethylamine in the Syrian golden hamster

Abstract

The single-dose toxicokinetics of N-nitrosodimethylamine (NDMA) has been characterized in 8-week-old male Syrian golden hamsters by analysis using high performance liquid chromatography of serial blood samples. An i.v. bolus dose of 4.2 mumols/kg [14C]NDMA revealed biphasic first-order elimination with a terminal half-life of 8.7 +/- 1.0 min (mean +/- SE) for unchanged NDMA and 31.5 +/- 5.5 min for total radioactivity, and evidence for conversion to polar metabolites was seen in the chromatographic assays. The systemic blood clearance and apparent steady-state volume of distribution for unchanged NDMA were 51.2 +/- 3.0 ml/min/kg and 582 +/- 60 ml/kg, respectively. No unchanged NDMA was detected in the urine following an i.v. bolus dose of 15 mumols/kg [14C]NDMA, but 31% of the total radioactivity was eliminated by that route. A dose of 38 mumols/kg given by gavage indicated a systemic bioavailability of 11 +/- 4% for unchanged NDMA. Reversible binding of NDMA to hamster plasma proteins was found to be negligible. Estimation of the intrinsic hepatic clearance (ClI) in the hamster produced a value of 648 ml/min/kg, which is greater than that previously obtained for the rat, and indicates that the metabolic capacity of the hamster liver is greater than that of the rat. These results suggest that this difference in ClI may play a role in the previously reported (Lijinsky et al. 1987) switch in organotropism from almost exclusivity for liver tumors in hamsters dosed by gavage to additional high incidences of lung and kidney tumors in the rat.