Central Nervous System Distribution of an Opioid Agonist Combination with Synergistic Activity.

Autor:	Griffith JI; Brain Barriers Research Center (J.I.G., M.K., A.S.M., S.R., W.F.E.), Department of Pharmaceutics (J.I.G., M.K., A.S.M., S.R., C.A.F., W.F.E.), Department of Pharmacology (D.J.B., C.A.F., G.L.W.), Department of Neuroscience (C.D.P., K.F.K., C.A.F., G.L.W.), and Department of Dermatology (G.L.W.), University of Minnesota, Minneapolis Elmquist Laboratory, Minneapolis, Minnesota grif0285@umn.edu elmqu011@umn.edu., Kim M; Brain Barriers Research Center (J.I.G., M.K., A.S.M., S.R., W.F.E.), Department of Pharmaceutics (J.I.G., M.K., A.S.M., S.R., C.A.F., W.F.E.), Department of Pharmacology (D.J.B., C.A.F., G.L.W.), Department of Neuroscience (C.D.P., K.F.K., C.A.F., G.L.W.), and Department of Dermatology (G.L.W.), University of Minnesota, Minneapolis Elmquist Laboratory, Minneapolis, Minnesota., Bruce DJ; Brain Barriers Research Center (J.I.G., M.K., A.S.M., S.R., W.F.E.), Department of Pharmaceutics (J.I.G., M.K., A.S.M., S.R., C.A.F., W.F.E.), Department of Pharmacology (D.J.B., C.A.F., G.L.W.), Department of Neuroscience (C.D.P., K.F.K., C.A.F., G.L.W.), and Department of Dermatology (G.L.W.), University of Minnesota, Minneapolis Elmquist Laboratory, Minneapolis, Minnesota., Peterson CD; Brain Barriers Research Center (J.I.G., M.K., A.S.M., S.R., W.F.E.), Department of Pharmaceutics (J.I.G., M.K., A.S.M., S.R., C.A.F., W.F.E.), Department of Pharmacology (D.J.B., C.A.F., G.L.W.), Department of Neuroscience (C.D.P., K.F.K., C.A.F., G.L.W.), and Department of Dermatology (G.L.W.), University of Minnesota, Minneapolis Elmquist Laboratory, Minneapolis, Minnesota., Kitto KF; Brain Barriers Research Center (J.I.G., M.K., A.S.M., S.R., W.F.E.), Department of Pharmaceutics (J.I.G., M.K., A.S.M., S.R., C.A.F., W.F.E.), Department of Pharmacology (D.J.B., C.A.F., G.L.W.), Department of Neuroscience (C.D.P., K.F.K., C.A.F., G.L.W.), and Department of Dermatology (G.L.W.), University of Minnesota, Minneapolis Elmquist Laboratory, Minneapolis, Minnesota., Mohammad AS; Brain Barriers Research Center (J.I.G., M.K., A.S.M., S.R., W.F.E.), Department of Pharmaceutics (J.I.G., M.K., A.S.M., S.R., C.A.F., W.F.E.), Department of Pharmacology (D.J.B., C.A.F., G.L.W.), Department of Neuroscience (C.D.P., K.F.K., C.A.F., G.L.W.), and Department of Dermatology (G.L.W.), University of Minnesota, Minneapolis Elmquist Laboratory, Minneapolis, Minnesota., Rathi S; Brain Barriers Research Center (J.I.G., M.K., A.S.M., S.R., W.F.E.), Department of Pharmaceutics (J.I.G., M.K., A.S.M., S.R., C.A.F., W.F.E.), Department of Pharmacology (D.J.B., C.A.F., G.L.W.), Department of Neuroscience (C.D.P., K.F.K., C.A.F., G.L.W.), and Department of Dermatology (G.L.W.), University of Minnesota, Minneapolis Elmquist Laboratory, Minneapolis, Minnesota., Fairbanks CA; Brain Barriers Research Center (J.I.G., M.K., A.S.M., S.R., W.F.E.), Department of Pharmaceutics (J.I.G., M.K., A.S.M., S.R., C.A.F., W.F.E.), Department of Pharmacology (D.J.B., C.A.F., G.L.W.), Department of Neuroscience (C.D.P., K.F.K., C.A.F., G.L.W.), and Department of Dermatology (G.L.W.), University of Minnesota, Minneapolis Elmquist Laboratory, Minneapolis, Minnesota., Wilcox GL; Brain Barriers Research Center (J.I.G., M.K., A.S.M., S.R., W.F.E.), Department of Pharmaceutics (J.I.G., M.K., A.S.M., S.R., C.A.F., W.F.E.), Department of Pharmacology (D.J.B., C.A.F., G.L.W.), Department of Neuroscience (C.D.P., K.F.K., C.A.F., G.L.W.), and Department of Dermatology (G.L.W.), University of Minnesota, Minneapolis Elmquist Laboratory, Minneapolis, Minnesota., Elmquist WF; Brain Barriers Research Center (J.I.G., M.K., A.S.M., S.R., W.F.E.), Department of Pharmaceutics (J.I.G., M.K., A.S.M., S.R., C.A.F., W.F.E.), Department of Pharmacology (D.J.B., C.A.F., G.L.W.), Department of Neuroscience (C.D.P., K.F.K., C.A.F., G.L.W.), and Department of Dermatology (G.L.W.), University of Minnesota, Minneapolis Elmquist Laboratory, Minneapolis, Minnesota grif0285@umn.edu elmqu011@umn.edu.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2022 Jan; Vol. 380 (1), pp. 34-46. Date of Electronic Publication: 2021 Oct 18.
DOI:	10.1124/jpet.121.000821
Abstrakt:	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 central nervous system (CNS) distribution. We performed intravenous and oral in vivo pharmacokinetic assessments of both drugs after 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 i.v. or 30 mg/kg orally to institute for cancer research (ICR) mice and 5 mg/kg i.v. to Friend leukemia virus strain B mice of the following genotypes: wild-type, breast cancer resistance protein ( Bcrp -/- ) (Bcrp knockout), Mdr1a/b -/- [P-glycoprotein (P-gp) knockout], and Bcrp -/- Mdr1a/b -/- (triple knockout). In the combination, clearance of oxymorphindole (OMI) was reduced by approximately half, and the plasma area under the concentration-time curve (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 have yet to be replaced as 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 µ -opioid receptor agonist is largely excluded from the CNS. (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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