DOSE-DEPENDENT PHARMACOKINETICS OF ALL-TRANS-RETINOIC ACID

Background: Orally administered all-trans-retinoic acid (all-trans-RA) can induce remission in a high proportion of patients with acute promyelocytic leukemia. Purpose: To further define the drug's pharmacokinetics, a study of intravenous all-trans-RA was performed in rhesus monkeys. Methods: A total of nine monkeys received intravenous bolus injections of all-trans-RA. Three different doses (20, 50, and 100 mg/m2) were each tested in three monkeys. Blood samples for determination of all-trans-RA concentration were obtained prior to drug administration and at 5, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, 360, and 480 minutes after drug administration. Results: Plasma disappearance of all-trans-RA was characterized by three distinct phases: a brief, initial exponential decline, followed by a relative plateau in the disappearance curve (the duration of which was dose dependent), and finally a terminal exponential decay. This profile is consistent with a capacity-limited (saturable) elimination process. The first-order (terminal) half-life for all-trans-RA averaged 19 minutes, and the mean clearances were 77, 52, and 59 mL/min for the 20-, 50-, and 100-mg/m2 dose groups, respectively. The mean +/- SD Michaelis constant (K(m)) for the capacity-limited process was 3.2 +/- 1.9-mu-M. Conclusions: Peak plasma concentrations following oral administration of 45 mg/m2 all-trans-RA in humans approach the K(m) for the capacity-limited process; thus, the dose-dependent pharmacokinetics of all-trans-RA described here may occur within the clinically used dosage range.