Differences in ocular tissue metabolism of WP-1303 (H-1129, a novel antiglaucoma agent) by species

Abstract

Purpose : To investigate the pharmacokinetic profile of WP-1303 (H-1129) in liver and ocular tissues.

Methods : Hepatocytes (1 × 10⁶ cells/mL) from rabbits, monkeys and humans were incubated with [¹⁴C]WP-1303 (10 μmol/L) at 37°C for 60 min. S9 protein from each species of ocular tissue (conjunctiva(Cj), cornea(C), aqueous humor(AH) and iris-ciliary body(ICB)) were also incubated with [¹⁴C] WP-1303(10μmol/L) at 37°C for 60 min. Next, [¹⁴C] WP-1303 derived radioactivity was measured using the LC-RID/MS methodology. NADPH was added to the reaction mixture as necessary. S9 from rabbit Cj was incubated with WP-1303 (1mM) in the presence of Menadione(0.03-10μM), an aldehyde oxidase (AO) inhibitor, at 37°C for 6 min. then the metabolite concentration was measured. AO mRNA expression in rabbit conjunctiva was measured by real time PCR.

Results : Over 90% of WP-1303 was metabolized in hepatocytes from three species. On the other hand, 73%, 9 % and 6.3% of WP-1303 was metabolized in the S9 protein in the Cj of rabbits, monkeys and humans, respectively. Metabolism of WP-1303 in the S9 protein in the rabbit Cj was inhibited in a dose-dependent manner by AO inhibitor. Expression of AO mRNA was confirmed in the Cj in rabbits.

Conclusions : Significant difference in the metabolism of WP-1303 was observed by species in ocular tissue but not in hepatocytes. Metabolism of WP-1303 was especially significant in rabbit Cj and mediation by AO is suggested.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.