A DOSE-RANGING PHARMACOKINETICS STUDY OF SODIUM DIETHYLDITHIOCARBAMATE IN NORMAL HEALTHY-VOLUNTEERS

Sodium diethyldithiocarbamate (DDTC) is an investigational modulator o f the toxicity produced by cisplatin. The pharmacokinetics of DDTC wer e evaluated after administration of 200 mg/m(2)/hr (n=8) and 400 mg/m( 2)/hr (n=7) DDTC as 4-hour intravenous infusions to normal male health y volunteers, Diethyldithiocarbamate concentration at steady-state (Cp ss) increased disproportionally from 27.0 +/- 7.6 mu M for the low dos e to 74.8 +/- 19.3 mu M for the high dose, whereas total body clearanc e decreased from 23.83 +/- 8.23 mL/min/kg for the low dose to 15.48 +/ - 2.72 mL/min/kg for the high dose (P < 0.05). However, the volume of distribution in the terminal phase remained unchanged. Diethyldithioca rbamate terminal elimination half-life (t(1/2 beta)) increased from 3. 74 +/- 1.10 minutes for the low dose to 6.08 +/- 1.07 minutes for the high dose (P < 0.005), The data were then fitted using a one-compartme nt open model with zero-order infusion and Michaelis-Menten eliminatio n kinetics, The Km for DDTC was estimated to be 124.3 +/- 19.9 mu M, w hereas the Vm was estimated to be 3.67 +/- 1.15 mu mol/min/kg. However , DDTC t(1/2 beta) was independent of DDTC concentrations, suggesting that the nonlinearity in DDTC kinetics does not exactly follow Michael is-Menten elimination kinetics. Thus, DDTC pharmacokinetics are dose d ependent and may not be concentration dependent. Clinically, DDTC Cpss will increase nonlinearly with an increase in dose.