Pharmacokinetics and metabolism in mouse retina of bis-allylic deuterated docosahexaenoic acid (D-DHA), a new dry AMD drug candidate

Abstract

Docosahexaenoic acid (DHA; 22:6n-3) rich photoreceptors function in a highly oxidizing microenvironment. Lipid peroxidation and inflammation contribute to initiation and progression of eye diseases including age-related macular degeneration (AMD). Deuteration of DHA at the bis-allylic positions (D-DHA) increases its resilience to oxidative damage in vitro. We studied the pharmacokinetics of dietary D-DHA as a therapy for replacing natural retinal DHA in vivo. Mice were fed 0.5% D-DHA for 77 days then switched to natural DHA (H-DHA) for 74 days. Tissue were harvested for analyses at various time points. D-DHA substitution levels were 75%–80% in the CNS and above 90% in all other tissues by day 77. D-DHA accretion was rapid in plasma and liver (t1/2a ∼2.8 d), followed by heart and red blood cells (t1/2a ∼8.5 d), then ocular tissues (choroid-RPE, neural retina, and optic nerve with t1/2a of 10.1, 23.4, and 26.3 days, respectively), while CNS accretion was slowest (t1/2a of 29.0–44.3 days). D-DHA elimination rates were comparable to, or slower than, accretion rates except for optic nerve. Retina had very long chain D-PUFA (D-VLC-PUFA) with 5 and 6 double bonds up to C36, as well as D-EPA and D-DPA derived metabolically from D-DHA. The neural retina and optic nerve reached the therapeutic target window (20%–50%) in 2–4 weeks. Biosynthesis of D-VLC-PUFA is consistent with normal metabolism. D-DHA crosses the blood-retina-barrier, enters visually active tissues, and is metabolized as its natural DHA parent where, as shown previously (Liu et al., 2022), it protects against lipid peroxidation.