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

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, including 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 (t 1/2 pi = 1.2 h) with peak plasma levels at 2.4 h; the concentrations then declined with exponential elimination from the central compartment (t 1/2 e = 3 h). The maximum concentrations of circulating radioactive compound or metabolites after 100 micrograms/kg [3H]2-TTNPB occurred in liver greater than fetus greater than adrenal greater than lung approximately equal to kidney greater than plasma; after 1000 micrograms/kg, maternal liver accumulated the highest concentration followed by plasma greater than fetus = placenta = uterus. An unidentified, polar metabolite was detected in plasma at 0.5 h and by 12 h constituted greater than 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.

Determination of arotinoid acid in human plasma by liquid chromatography–tandem mass spectrometry

“…Arotinoid acid [Ro 13-7410, (E)-4- [2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid] is among the most potent retinoids ever synthesized and has a high affinity to cellular retinoic acid-binding proteins. This accounts not only for its antipsoriatic activity in the treatment of a variety of skin diseases including severe acne, psoriasis and genodermatosesone [6,7], but also for its toxicity as a teratogen [8,9]. It belongs to the third generation of synthetic retinoids that may be effective in extremely low doses, and it is currently undergoing clinical investigation.…”