Stereoselectivity in pharmacokinetics of rivoglitazone, a novel peroxisome proliferator-activated receptor γ agonist, in rats and monkeys was examined. The pharmacokinetic model involving chiral inversion explained well the plasma profiles of R-isomer and S-isomer after intravenous and oral administration of (R)-rivoglitazone or (S)-rivoglitazone to rats and monkeys. The high stereoselectivity was evaluated in chiral inversion clearance (R/S ratio: 7.92), metabolic clearance (5.78), and volume of distribution (4.04) in rats; however, these were low (1.73, 1.31, and 1.06) in monkeys. The stereoselectivity in chiral inversion was also observed in in vitro incubation studies in plasma, and the R/S ratio of chiral inversion showed high correlation with the R/S ratio of plasma unbound fraction. The metabolic clearance of the primary five metabolic pathways of rivoglitazone was evaluated from an in vitro-in vivo extrapolation approach using rat and monkey liver microsomes. The high stereoselectivity in metabolic clearance in rat was evaluated (R/S ratio: 5.78), which was assumed to be because of the stereoselectivity in plasma unbound fraction, on the contrary, that in monkeys exhibited low stereoselectivity (0.774). Thus, the stereoselectivity in plasma unbound fraction was estimated to be a major determinant of stereoselectivity in pharmacokinetics of rivoglitazone in rats and monkeys.
Keywords: chiral inversion; distribution; in vitro-in vivo extrapolation (IVIVE); intrinsic clearance; metabolic clearance; metabolism; pharmacokinetics; protein binding; stereoselectivity; unbound fraction.
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