title: Time- and dose-dependent kinetics of all-trans-retinoic acid in rats after oral or intravenous administration(s).
abstract: The kinetics of all-trans-retinoic (RA) acid are known to be nonlinear. To clarify the mechanisms involved, RA kinetics were determined in four groups of rats: group 1 received a single 2-mg RA dose intravenously (N = 5); group 2 received the same treatment as group 1 after 12 days 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 chromatography. Noncompartmental analysis showed that RA disposition after intravenous bolus dosing obeyed Michaelis-Menten (MM) kinetics in group 1 (no pretreatment) and linear kinetics in group 2 (pretreated), with a lower area under the concentration vs. time curve, which suggested time-dependent kinetics with autoinduction. The same autoinduction phenomenon was observed after oral dosing in groups 3 and 4. Moreover, the mean area under the concentration vs. time curve was not higher after 5 mg dosing than after 2 mg dosing, which indicated a saturable mechanism of absorption. Fitting the data to a three-compartment model with saturable absorption and elimination kinetics confirmed the autoinduction of RA elimination (maximal velocity of elimination = 3330 vs. 541 micrograms/hr, p = 0.006, MM constant KMe = 7.53 vs. 1.10 micrograms/ml, p = 0.006) after 12 days RA administration, and an MM absorption mechanism resulting 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 micrograms/hr (group 4) (p = 0.02). The volume of distribution also decreased after pretreatment, which indicated a modification in tissular distribution (565 vs. 358 ml, p < 0.001, group 3 vs. 4).
authors.affiliation: Départment de Pharmacotoxicologie, Hôpital Avicenne, Bobigny, France.
authors.forename: S
authors.initials: S
authors.lastname: el Mansouri
authors.forename: M
authors.initials: M
authors.lastname: Tod
authors.forename: M
authors.initials: M
authors.lastname: Leclerq
authors.forename: O
authors.initials: O
authors.lastname: Petitjean
authors.forename: G
authors.initials: G
authors.lastname: Perret
authors.forename: M
authors.initials: M
authors.lastname: Porthault
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005069:Evaluation Studies as Topic; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014212:Tretinoin / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D014212:Tretinoin