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Pharmacokinetics of N-Nitrosodimethylamine in Beagles¹

Department of Drug Metabolism, Smith Kline & French Laboratories, Swedeland, Pennsylvania 19479 [C. T. G.], and Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122 [H. M. P., G. W. H.]

The pharmacokinetics of N-nitrosodimethylamine (NDMA) has been studied in beagles. Four male beagles were given 0.5- and 1.0-mg/kg doses of NDMA i.v. and 1.0- and 5.0-mg/kg doses of NDMA i.v. and 1.0- and 5.0-mg/kg doses p.o., and at appropriate times after dosing blood samples were drawn and the concentration of NDMA was measured. The experiments were separated by at least 1 week. Following a bolus i.v. dose, the concentration of NDMA in blood declined biphasically with a mean distribution half-life of 19 min and a mean elimination half-life of 73 min. The areas under the blood concentration versus time curves were proportional to the dose indicating that the pharmacokinetics in this dose range were first order. The mean systemic clearance was 43.3 ml/min/kg, the volume of distribution at steady state was 1.9 liters/kg and the mean residence time was 45 min. The clearance of NDMA in the dog was entirely metabolic because no NDMA could be detected in urine after i.v. dosing. The areas under the curve and maximum concentration in blood after the two p.o. doses were not proportional to dose. The evidence suggests that the pharmacokinetics of the 1.0-mg/kg dose were first order, but at the 5.0-mg/kg dose the metabolism of NDMA was saturated. The bioavailability of the lower p.o. dose (i.e., the fraction of the dose that reached the systemic circulation) averaged 93%. The high bioavailability was unexpected since, in the rat, the bioavailability of NDMA is only about 10%, and the systemic clearance in the dog exceeds hepatic blood flow. These data suggest that a substantial fraction of the systemic clearance in extrahepatic and that the pharmacokinetics of NDMA in higher species may be quite different from that observed in rodents.

¹ This work was supported in part by NIH Grant CA18618.

² To whom requests for reprints should be addressed.

Received 7/29/86. Revised 10/ 1/86. Accepted 10/ 8/86.