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

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Abstract
Tritiated tetrahydro-tetramethyl-naphthalenyl-propenyl benzoic acid (TTNPB; Ro 13-7410) was administered as a single oral bolus to pregnant hamsters (day 8) to determine the maternal plasma pharmacokinetic profile and peripheral tissue distribution patterns. Blood and tissue, deluding embryo or fetus, were collected at specific time intervals to 96 h and assayed for total radioactive compounds and/or parent retinoid. No lag time was required to describe retinoid absorption (t1/2 π=1.2 h) with peak plasma levels at 2.4 h; the concentrations then declined with exponential elimination from the central compartment (t i/2e = 3 h). The maximum concentrations of circulating radioactive compound or metabolites after 100 μg/kg [3H]2-TTNPB occurred in liver>fetus>adrenal>lung≈kidney>plasma; after 1000 μg/kg, maternal liver accumulated the highest concentration followed by plasma>fetus=placenta=uterus. An unidentified, polar metabolite was detected in plasma at 0.5 h and by 12 h constituted >90% of the total circulating radioactivity. TTNPB was absorbed and cleared more slowly, concentrated in the conceptus to a higher degree and possessed greater intrinsic activity than the naturally-occurring tetraene retinoids. These properties contribute to the marked teratogenic activity of TTNPB as compared to the tetraene retinoids.