Received for publication August 14, 2006.
Revised September 11, 2006.
Accepted for publication September 26, 2006.

The Disposition and Metabolism of Naveglitazar, a Peroxisome Proliferator-activated Receptor (PPAR) - dual, -dominant agonist in Mice, Rats, and Monkeys

Abstract

Naveglitazar (LY519818) is a non-thiozolidinedione peroxisome proliferator-activated receptor (PPAR) - dual, -dominant agonist that has shown glucose lowering potential in animal models and in the clinic. Studies have been conducted to characterize the disposition, metabolism, and excretion of naveglitazar in mice, rats, and monkeys after oral and/or intravenous (IV) bolus administration. Following oral administration of [¹⁴C]naveglitazar, naveglitazar was well absorbed and moderately metabolized in all species evaluated with total recoveries of radioactivity ranging from 90 to 96%. Naveglitazar was the most abundant peak observed in circulation at C_max representing 68 to 81% of the total radioactivity in plasma. The most prominent metabolite observed in circulation was the R-enantiomer of naveglitazar, LY591026, which is formed via enzymatic chiral inversion. Para-hydroxy naveglitazar and the sulfate conjugate of para-hydroxy naveglitazar were also observed in circulation in most species, especially in the monkey. The metabolic pathways observed include enzymatic chiral inversion, aromatic hydroxylation, oxidative dehydrogenation, and/or various phase II conjugation pathways. Naveglitazar was highly bound to plasma proteins among the species examined (> 99%) and binding was independent of concentration. Biliary excretion was recognized as the most prominent excretion pathway in bile-duct cannulated rats (79 out of the 96% recovered), producing an acyl glucuronide conjugate of naveglitazar and a sulfate and glucuronide diconjugate of para-hydroxy naveglitazar which were shown to be reversible. The primary excretory pathway observed in mice and monkeys was via the feces. In summary, naveglitazar was well absorbed, moderately metabolized, and excreted via the feces in mice, rats, and monkeys.

Key words: biliary excretion, excretion, mass spectrometry, metabolite identification, pharmacokinetics, phase II drug metabolism, plasma protein binding