TY - JOUR T1 - Pharmacological assessment of sepiapterin reductase inhibition on tactile response in the rat JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.257105 SP - jpet.119.257105 AU - James T Meyer AU - Brian A Sparling AU - William J McCarty AU - Maosheng Zhang AU - Marcus Soto AU - Stephen Schneider AU - Hao Chen AU - Jonathan Roberts AU - Helming Tan AU - Thomas Kornecook AU - Paul Andrews AU - Charles G Knutson Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/05/20/jpet.119.257105.abstract N2 - There is an unmet medical need for non-opioid pain therapies in human populations; several pathways are under investigation for possible therapeutic intervention. Tetrahydrobiopterin (BH4) has received attention recently as a mediator of neuropathic pain. Recent reports have implicated sepiapterin reductase (SPR) in this pain pathway as a regulator of BH4 production. To evaluate the role of SPR inhibition on BH4 reduction, we developed analytical methods to monitor the relationship between the plasma concentration of test article and endogenous pterins and applied these in the rat spinal nerve ligation pain model. Sepiapterin is an endogenous substrate, which accumulates upon inhibition of SPR. In response to a potent inhibitor of SPR, plasma concentrations of sepiapterin increased proportionally with exposure. An indirect effect PK/PD model was developed to describe the relationship between the plasma PK of test article and plasma sepiapterin levels in the rat, which was used to determine an in vivo SPR IC50 value. Evaluation of SPR inhibition and mechanical allodynia was assessed coordinately with pterin biomarkers in plasma and at the site of neuronal injury (i.e., dorsal root ganglion). Upon QD p.o. administration for 3 consecutive days, unbound plasma concentrations of test article exceeded the unbound in vivo rat SPR IC90 throughout the dose intervals leading to a 60% reduction in BH4 in the dorsal root ganglion. Despite evidence for pharmacological modulation of the BH4 pathway, there was no significant effect on the tactile paw withdrawal threshold relative to vehicle-treated controls.SIGNIFICANCE STATEMENT N/A ER -