Lack of dose proportional pharmacokinetics for CI-937, an anthrapyrazole DNA intercalator, in mice.
The time course of CI-937, an anthrapyrazole DNA intercalator, was studied in plasma of mice after single intravenous doses of 1.2, 8, 12, and 15 mg/kg (1/10 the LD10, 2/3 the LD10, LD10, and LD50). CI-937 concentrations in plasma were determined by a sensitive radioimmunoassay capable of quantifying 0.1 ng/ml. Area under the plasma concentration-time curve increased less than proportionally to dose. Time-averaged plasma clearance was dose-dependent, increasing from 31.1 to 63.6 ml/min/kg over the 1.2 to 12 mg/kg dose range. Terminal half-life in plasma ranged from 11 to 25 days. Fraction plasma protein bound was 69 to 76% from 10 to 10,000 ng/ml, which suggests the nonlinear behavior was not due to saturable protein binding. Potential mechanisms include autoinduction of metabolism and dose-dependent reabsorption from the gastrointestinal tract or kidneys.
Wong
B
B
Pharmacokinetics/Drug Metabolism Department, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Nordblom
G
G
Chang
T
T
Whitfield
L
L
D000818:Animals; D000880:Anthraquinones / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D007364:Intercalating Agents / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D011485:Protein Binding; D011720:Pyrazoles / Q000097:blood / Q000493:pharmacokinetics*; D011863:Radioimmunoassay
D000880:Anthraquinones; D007364:Intercalating Agents; D011720:Pyrazoles; C046658:teloxantrone