Comparative distribution, pharmacokinetics and placental permeabilities of all-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, retinyl acetate and 9-cis-retinal in hamsters

Abstract

Pregnant hamsters were given a single oral dose (35 mumol/kg) of all-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, 9-cis-retinal or all-trans-retinyl acetate during the early primitive streak stage of development. The radioactivity associated with the acidic retinoids was distributed to all tissues sampled (including placenta and fetus), with the largest accumulation in the liver and the least accumulation in fat. Radioactivity from 9-cis-retinal or retinyl acetate concentrated in the liver and lung. The all-trans-retinoic acid was oxidized in vivo to all-trans-4-oxo-retinoic acid and isomerized to 13-cis-retinoic acid: 13-cis-retinoic acid was oxidized to 13-cis-4-oxo-retinoic acid and isomerized to all-trans-retinoic acid. No parent 9-cis-retinal or retinyl acetate could be detected in maternal plasma. Plasma concentrations of the parent acidic retinoids reached their maxima within 60 min and then followed exponential decay. Of all the retinoids examined here, 13-cis-retinoic acid showed the largest area under the plasma curve, the slowest clearance and the longest elimination t1/2. Total plasma radioactivity, consisting of unidentified metabolites, remained elevated at 4 days after dosing. Maternal peak circulating concentrations of the parent retinoids, total radioactivity, plasma pharmacokinetic parameters or the total concentrations of residual radioactivity in fetal tissues could not be correlated with the differential teratogenic potencies of these retinoids.

Pharmacokinetics, tissue distribution and placental permeability of tetrahydro-tetramethyl-naphthalenyl-propenyl benzoic acid (a retinoidal benzoic acid derivative) in hamsters

“…The presence of the polar TTNPB metabolite in hamster plasma is consistent with the pattern of microsome-mediated oxidation of the tetraene retinoids in hamsters (21); the identification of this metabolite was beyond the scope of the present study.…”

“…Following 35 lJIlloIJkg of all-trans-or 13-cis-retinoic acid given in an identical protocol, the parent tetraene retinoids declined to nondetectable concentrations in maternal plasma within 4 or 12 h, respectively (21). Although the molar doses of TfNPB studied here were only O.OI-Q.lx those of the tetraene retinoids, parent TTNPB persisted in maternal plasma for up to 24 h. Both the naturally-occurring and TfNPB retinoids were biotransfonned rapidly and extensively.…”

“…The parent TTNPB achieved mean plasma Cmax later, but it represented a much greater percentage of the total administered dose (70%) compared to the tetraene retinoids (8%) (21).…”

“…The much larger relative maternal plasma AUC for TTNPB as compared to all-trans-retinoic acid (21) can be accounted for in the protracted elimination phase.…”

Characterization of heterologously expressed recombinant retinoic acid receptors with natural or synthetic retinoids

“…Modification in the P-cyclogeranylidene ring had a little influence on the binding affinity (Ro 12-4824; Table 2). Ro 12-4824 is a product of RA metabolism and is biologically active (31,32). Our displacement assay shows that 4-0x0all-trans-RA binds to RARa and RARP in a manner similar to that of the parent compound, all-trans-RA.…”