PT  - JOURNAL ARTICLE
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 S. Andrews
AU  - Charles G. Knutson
TI  - Pharmacological Assessment of Sepiapterin Reductase Inhibition on Tactile Response in the Rat
AID  - 10.1124/jpet.119.257105
DP  - 2019 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 476--486
VI  - 371
IP  - 2
4099  - http://jpet.aspetjournals.org/content/371/2/476.short
4100  - http://jpet.aspetjournals.org/content/371/2/476.full
SO  - J Pharmacol Exp Ther2019 Nov 01; 371
AB  - There is an unmet medical need for nonopioid 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 pharmacokinetic/pharmacodynamic model was developed to describe the relationship between the plasma pharmacokinetics of test article and plasma sepiapterin levels in the rat, which was used to determine an in vivo SPR IC50 value. SPR inhibition and mechanical allodynia were assessed coordinately with pterin biomarkers in plasma and at the site of neuronal injury (i.e., dorsal root ganglion). Upon daily oral 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.