The structurally novel macrocyclic tetrapeptide cyclo[Pro-Sar-Phe-D-Phe] exhibits mixed mu and kappa opioid receptor agonist and selective kappa antagonist activity without the classical side-effects associated with µ opioid agonists. Because of its promising efficacy-safety profile and activity following oral administration to mice, the pharmacokinetic properties of the peptide were evaluated to facilitate its further development. The peptide exhibited favorable metabolic stability (t1/2 = ~120 min) in mouse liver microsomes and undergoes metabolism primarily via cytochrome P450 isoform CYP3A4 (t1/2 &gt;120 min), along with minor metabolism (~20%) by CYP2C19. Importantly, the peptide was devoid of any inhibition of the most common drug metabolizing human isoforms CYP3A4, 2D6, 2C9, 2C19, and 1A2 (IC50 &gt;100 µM). It also showed moderate plasma protein binding (~50%). Following oral administration to mice at 60 mg/kg, the peptide achieved a maximum concentration of 1470 ng/mL in plasma and 290 ng/g in brain, but undergoes rapid absorption and elimination with half-lives of 1.9 and 1.8 hours in plasma and brain, respectively. The results showed the peptide possesses some favorable pharmacokinetic properties and has emerged as a promising lead for potential treatments of pain and/or addiction. The results of this pharmacokinetic study will be presented.

Preclinical evaluation of the orally bioavailable macrocyclic mixed opioid agonist/antagonist tetrapeptide cyclo[Pro-Sar-Phe-D-Phe]

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ACS Fall 2022

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