TIME-DEPENDENT AND DOSE-DEPENDENT KINETICS OF ALL-TRANS-RETINOIC ACIDIN RATS AFTER ORAL OR INTRAVENOUS ADMINISTRATION(S)

The kinetics of all-trans-retinoic (RA) acid are known to be nonlinear . To clarify the mechanisms involved, RA kinetics were determined in f our groups of rats: group 1 received a single 2-mg RA dose intravenous ly (N = 5); group 2 received the same treatment as group 1 after 12 da ys of oral RA (2 mg/day) (N = 6); group 3 received a single, oral 2-mg (N = 6) or 5-mg RA dose (N = 6); and group 4 (N = 5 + 3) received the same treatment as group 3 after 12 days of oral RA (2 mg/day). Blood samples, 10-12/animal, were taken during the 7 hr following the final dosage, plasma RA concentrations were determined by liquid chromatogra phy. Noncompartmental analysis showed that RA disposition after intrav enous bolus dosing obeyed Michaelis-Menten (MM) kinetics in group 1 (n o pretreatment) and linear kinetics in group 2 (pretreated), with a lo wer area under the concentration vs. time curve, which suggested time- dependent kinetics with autoinduction. The same autoinduction phenomen on was observed after oral dosing in groups 3 and 4. Moreover, the mea n area under the concentration vs. time curve was not higher after 5 m g dosing than after 2 mg dosing, which indicated a saturable mechanism of absorption. Fitting the data to a three-compartment model with sat urable absorption and elimination kinetics confirmed the autoinduction of RA elimination (maximal velocity of elimination = 3330 vs. 541 mu g/hr, p = 0.006, MM constant K-Mo = 7.53 vs. 1.10 mu g/ml, P = 0.006) after 12 days RA administration, and an MM absorption mechanism result ing in a saturable absorption (bioavailability F = 0.58 at 2 mg vs, 0. 25 at 5 mg, group 3) that decreased after 12 days of RA treatment: the maximal velocity of absorption decreased from 1632 (group 3) to 631 m u g/hr (group 4) (p = 0.02). The volume of distribution also decreased after pretreatment, which indicated a modification in tissular distri bution (565 vs, 358 ml, p < 0.001, group 3 vs. 4).