PHARMACOKINETICS OF 13-CIS-, ALL-TRANS-, 13-CIS-4-OXO-, AND ALL-TRANS-4-OXO RETINOIC ACID AFTER INTRAVENOUS ADMINISTRATION IN THE CYNOMOLGUS MONKEY

The intravenous pharmacokinetics of 13-cis-, all trans-, 13-cis-4-oxo, and all-trans-4-oxo retinoic acid (RA) were determined in nonpregnant female cynomolgus monkeys. All-trans- and 13-cis-RA were injected at two doses (0.25 or 0.0125 mg/kg) end all-trans-4-oxo RA and 13-cis-4-o xo RA at 0.25 mg/kg. Total body clearance, volume of distribution, and volume of distribution at steady state of all-trans-RA were dose-depe ndent with greater values at the lower dose. Elimination half life was longer for the cis-compounds and not dose-dependent (N = 1 for 13-cis -4-oxo RA, N = 3 for other compounds, harmonic mean +/- pseudostandard deviation, min): 13-cis-4-oxo RA (837) greater than or equal to 13-ci s-RA (301 +/- 204). all-trans-PA (38 e 3), all-trans-4- oxo RA (11 +/- 2). Secondary plasma peaks were noted only after administration of 13 -cis-4-oxo RA. The low area under the time concentration curves for ob servable metabolites after intravenous injection of the oxidated compo unds suggests further metabolism plays a minimal role in the eliminati on of these compounds from the monkey. Plasma-time concentration curve s were fitted to multicompartmental models and suggested <30% of each compound was available in the central compartment for elimination in t he postdistribution phase. A comparison of the kinetics of the isomers indicated oxidation of all-trans-RA to all-trans-4-oxo RA increased m ean total body clearance values 4-fold. Elimination half-life was long er and volume of distribution was greater for 13-cis-RA compared with all trans-RA in the cynomolgus monkey. The similarity of RA pharmacoki netics and teratogenic susceptibility in the human, monkey, and hamste r may be related to similarities in volume distribution and biotransfo rmation.