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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

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Abstract

Pregnant hamsters were given a single oral dose (35 μmol/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 t 1/2. 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.

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Author notes

  1. W. Brian Howard

    Present address: Pharmaceutical Research Department, F. Hoffmann-La Roche & Co. Ltd., CH-4002, Basel, Switzerland

Authors and Affiliations

  1. Center for Environmental Toxicology, UMC 5600, Utah State University, 84322, Logan, Utah, USA

    W. Brian Howard

  2. Department of Health Services, State of California, 5850 Shellmound, 94608, Emoryville, CA, USA

    Calvin C. Willhite

  3. Toxicology Division, Letterman Army Institute of Research, 94129, Presidio of San Francisco, CA, USA

    Stanley T. Omaye

  4. Center for Environmental Toxicilogy, UMC 5600, Utah State University, 84322, Logan, Utah, USA

    R. P. Sharma

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  1. W. Brian Howard
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  2. Calvin C. Willhite
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  3. Stanley T. Omaye
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  4. R. P. Sharma
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Howard, W.B., Willhite, C.C., Omaye, S.T. et al. 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. Arch Toxicol 63, 112–120 (1989). https://doi.org/10.1007/BF00316432

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  • DOI: https://doi.org/10.1007/BF00316432

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