Fig. 8: Pharmacokinetic and pharmacodynamic evaluation of AG10-Oxycodone conjugate (AG10-L2-Oxy). | Nature Communications

Fig. 8: Pharmacokinetic and pharmacodynamic evaluation of AG10-Oxycodone conjugate (AG10-L2-Oxy).

From: Peripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects

Fig. 8

a Pharmacokinetic profile of AG10-L2-Oxy and oxycodone after a single subcutaneous dose of 16 µmol/kg to rats (n = 4 per group). Plasma concentration of compounds is expressed as means ± s.d. of three biological replicates. b Brain to plasma ratios and c cerebrospinal fluid (CSF) to plasma ratios of AG10-L2-Oxy and oxycodone (n = 3 per group). Male rats were dosed subcutaneously with 16 µmol/kg (equivalent to 5 mg/kg) oxycodone and both 16 and 64 µmol/kg AG10-L2-Oxy (equivalent to 13 mg/kg and 52 mg/kg, respectively). The plasma, brain tissue, and CSF were collected at 60 min after dosing. The ratio of the brain (ng/g) versus plasma concentration (ng/mL) is expressed as the percentage brain to plasma ratio. The ratio of the CSF (ng/mL) versus plasma concentration (ng/mL) is expressed as the percentage CSF to plasma ratio. Bar graphs show the respective mean (±s.d.) (n = 3 per group). Statistical differences were determined using One Way ANOVA followed by Tukey’s post-hoc test (*P < 0.05 compared to oxycodone 16 µmol/kg group). For the brain to plasma ratio experiment F(2,6) = 577.6, P < 0.0001 and for the CSF to plasma ratio experiment F(2,6) = 68.84, P < 0.0001. d Hot plate latency and e GI transit assays to evaluate the contribution of opioid agonists on central and peripheral mu-opioid receptors in OIC. Oxycodone (16 µmol/kg; subcutaneous route, SC), Oxycodone (640 and 1280 nmol per rat; intracerebroventricular route, ICV), AG10-L2-Oxy (64 µmol/kg; subcutaneous route, SC), AG10-L2-Oxy (160 nmol per rat; intracerebroventricular route, ICV), or vehicle was administered at t = 0 min. Charcoal was given at 10 min. Hot plate latency and GI transit were measured at 40 min. Bar graph showing the respective mean (±s.d.) (n = 5 rats per group). Statistical differences were determined using one-way ANOVA followed by Tukey’s post-hoc test (*P < 0.05). F(5,24) = 300.5, P < 0.0001 for the hot plate assay and F(5,24) = 983.3, P < 0.0001 for the GI transit assay. Source data are provided as a Source Data file.

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