Absorption, Distribution, Metabolism, and Excretion of [¹⁴C]GDC-0449 (Vismodegib), an Orally Active Hedgehog Pathway Inhibitor, in Rats and Dogs: A Unique Metabolic Pathway via Pyridine Ring Opening

Abstract

ABSTRACT:2-Chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(methylsulfonyl)-benzamide (GDC-0449, vismodegib) is a potent and selective first-inclass small-molecule inhibitor of the Hedgehog signaling pathway and is currently in clinical development. In this study, we investigated the metabolic fate and disposition of GDC-0449 in rats and dogs after a single oral administration of [ 14 C]GDC-0449. An average of 92.4 and 80.4% of the total administered radioactivity was recovered from urine and feces in rats and dogs, respectively. In both species, feces were the major route of excretion, representing 90.0 and 77.4% of the total dose in rats and dogs, respectively. At least 42.1 and 30.8% of the dose was absorbed in rats and dogs, respectively, based on the total excretion of radioactivity in bile and urine. GDC-0449 underwent extensive metabolism in rats and dogs with the major metabolic pathways being oxidation of the 4-chloro-3-(pyridin-2-yl)-phenyl moiety followed by phase II glucuronidation or sulfation. Three other metabolites resulting from an uncommon pyridine ring opening were found, mainly in feces, representing 1.7 to 17.7% of the dose in total in rats and dogs. In plasma, the total radioactivity was absorbed quickly in both rats and dogs, and unchanged GDC-0449 was the predominant circulating radioactive species in both species (>95% of total circulating radioactivity). Quantitative whole-body autoradiography in rats showed that the radioactivity was well distributed in the body, except for the central nervous system, and the majority of radioactivity was eliminated from most tissues by 144 h.

Investigations into the Mechanisms of Pyridine Ring Cleavage in Vismodegib

“…In previous in vivo studies, vismodegib was shown to form three pyridine ring-opened metabolites M9, M13, and M18 (Graham et al, Yue et al, 2011). These metabolites were excreted mainly in feces, with the greatest amount in the dog (15%), followed by similar amounts in the excreta of human and rat (;5%).…”

“…An aliquot of a rat bile sample was extracted with ethyl acetate, and the organic phase was removed and dried as previously reported (Yue et al, 2011). The sample was reconstituted in 18 O-water with or without sulfuric acid (0.5 N).…”

“…In addition to simple oxidative products on the pyridine and chlorophenyl rings to form phenol-type metabolites, three pyridine ring cleavage metabolites were found in excreta (Yue et al, 2011) (Fig. 1).…”

“…The literature precedence for such a reaction is limited. These metabolites were designated M9, M13, and M18 and were characterized using high-resolution mass spectrometry (MS) and, in the case of M13, also by 1 H NMR (Yue et al, 2011). Different amounts of these metabolites were found in the excreta of each species.…”

“…We previously reported the identification and characterization of vismodegib's metabolites (Wong et al, 2009(Wong et al, , 2010Graham et al, 2011b;Yue et al, 2011). After a single dose of 14 C-vismodegib, the radioactivity was predominately excreted in feces (80%-90% in rat, dog, and healthy human subjects), partly as unabsorbed material.…”