CNS Distribution of an Opioid Agonist Combination with Synergistic Activity.

Novel combinations of specific opioid agonists like loperamide and oxymorphindole targeting the µ- and δ-opioid receptors, respectively, have shown increased potency with minimized opioid-associated risks. However, whether their interaction is pharmacokinetic or pharmacodynamic in nature has not been determined. This study quantitatively determined whether these drugs have a pharmacokinetic interaction that alters systemic disposition or CNS distribution. We performed IV and oral in vivo pharmacokinetic assessments of both drugs following discrete dosing and administration in combination to determine whether the combination had any effect on systemic pharmacokinetic parameters or CNS exposure. Drugs were administered at 5 or 10 mg/kg IV or 30 mg/kg orally to ICR mice, and 5 mg/kg IV to FVB mice of the following genotypes: wild-type, Bcrp-/- (Bcrp knockout, BKO), Mdr1a/b-/- (P-gp knockout, PKO), and Bcrp-/- Mdr1a/b-/- (triple knockout, TKO). In the combination, clearance of OMI was reduced by approximately half, and the plasma AUC increased. Consequently, brain and spinal cord AUCs for OMI in the combination also increased proportionately. Both loperamide and OMI are P-gp substrates, but administration of the two drugs in combination does not alter efflux transport at the CNS barriers. Because OMI alone shows appreciable brain penetration but little therapeutic efficacy on its own, and because loperamide's CNS distribution is unchanged in the combination, the mechanism of action for the increased potency of the combination is most likely pharmacodynamic, and most likely occurs at receptors in the peripheral nervous system. This combination has favorable characteristics for future development. Significance Statement Opioids are the most effective treatments for moderate-to-severe pain and chronic pain, but their side effects are dangerous. Combinations of opioids with peripheral activity, such as loperamide and oxymorphindole, would be valuable in that they are effective at much lower doses and have reduced risks for dangerous side effects, because the MOR-agonist is largely excluded from the CNS.