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) and all-trans-4-oxo RA and 13-cis-4-oxo 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-dependent 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) > or = 13-cis-RA (301 +/- 204) > all-trans-RA (38 +/- 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 observable metabolites after intravenous injection of the oxidated compounds suggests further metabolism plays a minimal role in the elimination of these compounds from the monkey. Plasma-time concentration curves were fitted to multicompartmental models and suggested < 30% of each compound was available in the central compartment for elimination in the postdistribution phase. A comparison of the kinetics of the isomers indicated oxidation of all-trans-RA to all-trans-4-oxo RA increased mean total body clearance values 4-fold.(ABSTRACT TRUNCATED AT 250 WORDS)
Sandberg
J A
JA
Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, AR 72079-9502.
Eckhoff
C
C
Nau
H
H
Slikker
W
W
D000818:Animals; D005260:Female; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D013997:Time Factors; D014212:Tretinoin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*
D014212:Tretinoin