Species-dependent metabolism of a novel selective α7 neuronal acetylcholine receptor agonist ABT-107

Abstract

1. Metabolism of ABT-107 was investigated in in vitro hepatic systems, in rat and monkey receiving [¹⁴C]ABT-107, and in vivo plasma in rat, dog, monkey and human.

2. In in vitro hepatic systems, ABT-107 was primarily cleared via oxidative metabolism, and proceeded via two parallel pathways. Pathway 1, ABT-107 was oxidized at the nitrogen of quinuclidine moiety to form M1. Pathway 2, oxidation occurred at indole-containing moiety to form M2. Metabolism via N-oxidation was predominant in dog and rat, while in monkey and human, metabolism proceeded primarily via oxidation of indole-containing moiety.

3. ABT-107 was extensively metabolized in vivo in rat and monkey. M1 was primarily found in rat urine and bile; whereas, M2 was the major metabolite in monkey urine and feces. M1 was the predominant circulating metabolite in dog and rat. M2 was the primary circulating metabolite in monkey and human.

4. Enzymatic studies suggested M1 formation was primarily mediated by renal FMO1. CYP3A4, 1A2, 2J2 and 2D6 were primary enzymes catalyzing M2 formation.

5. Biotransformation of ABT-107 in human and monkey is markedly different from that in dog and rat, suggesting that monkey is an appropriate model for predicting human biotransformation and toxicology of ABT-107.

• ABT-107
• cytochrome P450
• FMO
• species difference

Acknowledgements

We thank Dr Gary Robert (Radiosynthesis Group at GPRD, North Chicago, IL) for synthesis of [³H]ABT-107, Dr Srirajan Vaidyanathan for synthesis of [¹⁴C]ABT-107, Mr Jia Du for purification of [³H]ABT-107 and [¹⁴C]ABT-107, Dr Jianguo Ji (Neuroscience Discovery at GPRD, North Chicago, IL) for synthesis of ABT-107 and metabolites and Dr Girish Gudi and Mrs Jeanette Licata for the contribution to rat and monkey ADME studies.