Species differences in metabolism of a new antiepileptic drug candidate, DSP‐0565 [2‐(2′‐fluoro[1,1′‐biphenyl]‐2‐yl)acetamide]

Abstract

The metabolism and pharmacokinetics of DSP‐0565 [2‐(2′‐fluoro[1,1′‐biphenyl]‐2‐yl)acetamide], an antiepileptic drug candidate, was investigated in rats, dogs, and humans. In human hepatocytes, [14C]DSP‐0565 was primarily metabolized via amide bond hydrolysis to (2′‐fluoro[1,1′‐biphenyl]‐2‐yl)acetic acid (M8), while in rat and dog hepatocytes, it was primarily metabolized via both hydrolysis to M8 and hydroxylation at the benzene ring or the benzyl site to oxidized metabolites. After single oral administration of [14C]DSP‐0565 to rats and dogs, the major radioactivity fraction was recovered in the urine (71–72% of dose) with a much smaller fraction recovered in feces (23–25% of dose). As primary metabolites in their excreta, M8, oxidized metabolites, and glucuronide of DSP‐0565 were detected. The contribution of metabolic pathways was estimated from metabolite profiles in their excreta: the major metabolic pathway was oxidation (57–62%) and the next highest was the hydrolysis pathway (23–33%). These results suggest that there are marked species differences in the metabolic pathways of DSP‐0565 between humans and animals. Finally, DSP‐0565 human oral clearance (CL/F) was predicted using in vitro–in vivo extrapolation (IVIVE) with/without animal scaling factors (SF, in vivo intrinsic clearance/in vitro intrinsic clearance). The SF improved the underestimation of IVIVE (fold error = 0.22), but the prediction was overestimated (fold error = 2.4–3.3). In contrast, the use of SF for hydrolysis pathway was the most accurate for the prediction (fold error = 1.0–1.4). Our findings suggest that understanding of species differences in metabolic pathways between humans and animals is important for predicting human metabolic clearance when using animal SF.

Characterization of In Vitro and In Vivo Metabolism of Antazoline Using Liquid Chromatography-Tandem Mass Spectrometry

“…No data on ANT metabolism in humans is available, most likely because it was not required at the time of registration of the drug (Phenazolinum, Polfa, Poland) containing ANT mesylate. Species differences in metabolism are often responsible for the difficulties in extrapolating the metabolic data from laboratory animals to humans [19]. Food and Drug Administration (FDA) noted the cases for which clinically relevant metabolites have not been identified during preclinical development [16].…”

HPO-Shuffle: an associated gene prioritization strategy and its application in drug repurposing for the treatment of canine epilepsy

“…In terms of treatment for canine epilepsy, certain antiepileptic drugs effective in human beings, including phenytoin, valproic acid and carbamazepine, may not work the same in dogs due to species differnece in metabolism [3,4]. On the other hand, drugs used for canine epilepsy are also associated with adverse effects.…”