N-alkylprotoporphyrin formation and hepatic porphyria in dogs after administration of a new antiepileptic drug candidate: mechanism and species specificity.

ABSTRACT

A new antiepileptic synaptic vesicle 2a (SV2a) ligand drug candidate was tested in 4-week oral toxicity studies in rat and dog. Brown pigment inclusions were found in the liver of high-dose dogs. The morphology of the deposits and the accompanying liver changes (increased plasma liver enzymes, increased total hepatic porphyrin level, decreased liver ferrochelatase activity, combined induction, and inactivation of cytochrome P-450 CYP2B11) suggested disruption of the heme biosynthetic cascade. None of these changes was seen in rat although this species was exposed to higher parent drug levels. Toxicokinetic analysis and in vitro metabolism assays in hepatocytes showed that dog is more prone to oxidize the drug candidate than rat. Mass spectrometry analysis of liver samples from treated dogs revealed an N-alkylprotoporphyrin adduct. The elucidation of its chemical structure suggested that the drug transforms into a reactive metabolite which is structurally related to a known reference porphyrogenic agent allylisopropylacetamide. That particular metabolite, primarily produced in dog but neither in rat nor in human, has the potential to alkylate the prosthetic heme of CYP. Overall, the data suggested that the drug candidate should not be porphyrogenic in human. This case study further exemplifies the species variability in the susceptibility to drug-induced porphyria.