title: A dose-ranging pharmacokinetics study of sodium diethyldithiocarbamate in normal healthy volunteers.
abstract: Sodium diethyldithiocarbamate (DDTC) is an investigational modulator of the toxicity produced by cisplatin. The pharmacokinetics of DDTC were evaluated after administration of 200 mg/m2/hr (n = 8) and 400 mg/m2/hr (n = 7) DDTC as 4-hour intravenous infusions to normal male healthy volunteers. Diethyldithiocarbamate concentration at steady-state (Cpss) increased disproportionally from 27.0 +/- 7.6 microM for the low dose to 74.8 +/- 19.3 microM for the high dose, whereas total body clearance 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. Diethyldithiocarbamate terminal elimination half-life (t1/2 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-compartment open model with zero-order infusion and Michaelis-Menten elimination kinetics. The Km for DDTC was estimated to be 124.3 +/- 19.9 microM, whereas the Vm was estimated to be 3.67 +/- 1.15 mumol/min/kg. However, DDTC t1/2 beta was independent of DDTC concentrations, suggesting that the nonlinearity in DDTC kinetics does not exactly follow Michaelis-Menten elimination kinetics. Thus, DDTC pharmacokinetics are dose dependent and may not be concentration dependent. Clinically, DDTC Cpss will increase nonlinearly with an increase in dose.
authors.affiliation: Drug Evaluation Unit, Hennepin County Medical Center, Minneapolis, MN 55404.
authors.forename: W M
authors.initials: WM
authors.lastname: Awni
authors.forename: J V
authors.initials: JV
authors.lastname: Hoff
authors.forename: B E
authors.initials: BE
authors.lastname: Shapiro
authors.forename: C E
authors.initials: CE
authors.lastname: Halstenson
mesh_terms: D000328:Adult; D004050:Ditiocarb / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate
chemical_list: D004050:Ditiocarb