Talarozole

Talarozole (R115866) is an oral systemic all-trans retinoic acid metabolism blocking agent (RAMBA) which increases intracellular levels of endogenous all-trans retinoic acid (RA). Talarozole inhibits both CYP26A1 and CYP26B1 with IC₅₀s of 5.4 and 0.46 nM, respectively. IC50 & Target:IC50: 0.46/5.1 nM (CYP26B1/A1)^[1] In Vitro:When HepG2 cells are cotreated with atRA and Talarozole (1 μM), 4-OH-RA and 4-oxo-RA formation is significantly decreased^[2]. In Vivo:A maximum 84% inhibition of CYP26 activity at 0.5 hours post-dose is predicted based on Talarozole (TLZ) C_max of 80 nM and a K_i of 1 nM following a single dose of Talarozole. Due to the short Talarozole half-life (2.2 hrs) CYP26 activity is predicted to return to 100% by 12 hours. In agreement with the predictions, atRA concentrations are increased by 82, 63 and 60% at 4 hours post-dose in the serum, liver and testes, respectively, and concentrations returned to baseline by 24 hours. Following multiple doses of Talarozole, liver CYP26 mRNA and activity are increased suggesting autoinduction of CYP26 due to increased atRA concentrations. In agreement, atRA concentrations are elevated in serum and liver at all timepoints measured. This increase in atRA concentrations is associated with increased mRNA of the mitochondrial biogenesis markers PGC-1β and NRF-1 in comparison to control mice^[3].