Abstract
YL-IPA08, exerting rapid antidepressant-like and anxiolytic-like effects on behaviors by translocator protein (TSPO) mediation, is a novel compound that has been discovered and developed at our institute. Fit-for-purpose pharmacokinetic properties is urgently needed to be discovered as early as possible for a new compound. YL-IPA08 exhibited low bioavailability (∼6%) during the preliminary pharmacokinetics study in rats after oral administration. Our aim was to determine how metabolic disposition by microsomal P450 enzymes in liver and intestine limited YL-IPA08’s bioavailability and further affected brain penetration to the target. Studies of in vitro metabolic stability and permeability combined with in vivo oral bioavailability, panel CYP inhibitor co-administration via different routes, and double cannulation rats were conducted to elucidate the intestinal and hepatic first-pass effect of YL-IPA08 on bioavailability. Unbound brain-to-plasma ratio (K p,uu) in rats was determined at steady state. Results indicated that P450-mediated elimination appeared to be important for its extensive first-pass effect with comparative contribution of gut (35%) and liver (17%), and no significant species difference was observed. The unbound concentration of YL-IPA08 in rat brain (6.5 pg/ml) was estimated based on K p,uu (0.18) and was slightly higher than in vitro TSPO-binding activity (4.9 pg/ml). Based on the onset efficacy of YL-IPA08 toward TPSO in brain and K p,uu, therapeutic human plasma concentration was predicted to be ∼27.2 ng/ml would easily be reached even with unfavorable bioavailability.
Highlights
Major depressive disorder (MDD) is a chronic and debilitating disorder with high rates of medical and psychiatric co-morbidity
The quantification of YL-IPA08 in rat plasma was fully validated, and in vitro samples were validated by selectivity, precision, and stability
YL-IPA08 was discovered to be eliminated in liver microsomes and intestinal microsomes of rat and human to different extents in the presence of CYPs (NADPH) and/or UGTs (UDPGA) co-factors
Summary
Major depressive disorder (MDD) is a chronic and debilitating disorder with high rates of medical and psychiatric co-morbidity. It is well recognized that a drug with low oral bioavailability can be impacted by multiple factors including absorption barrier, intestinal and hepatic metabolism before going into systemic circulation (Fan et al, 2019). Both CYP and UGT enzymes are major drug metabolizing enzymes in gut and liver that facilitate the elimination of xenobiotics. The liver contains higher amount of CYPs and UGTs, the small intestine is usually exposed to higher concentration of xenobiotics Both liver and intestine play important roles in bioavailability (Ohno and Nakajin, 2009; Court et al, 2012; Karlsson et al, 2013). Several studies have demonstrated the relative importance of intestinal metabolism to low bioavailability, and the situations were substrate-dependent (Cubitt et al, 2009; Fan et al, 2019)
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