PT  - JOURNAL ARTICLE
AU  - Philip A Krieter
AU  - C. Nora Chiang
AU  - Shwe Gyaw
AU  - Phil Skolnick
AU  - Rebekah Snyder
TI  - Pharmacokinetic Interaction of Naloxone and Naltrexone Following Intranasal Administration to Healthy Subjects
AID  - 10.1124/dmd.118.085977
DP  - 2019 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.118.085977
4099  - http://dmd.aspetjournals.org/content/early/2019/04/16/dmd.118.085977.short
4100  - http://dmd.aspetjournals.org/content/early/2019/04/16/dmd.118.085977.full
AB  - Naloxone, a mu opioid receptor antagonist, is administered intranasally to reverse an opioid overdose but its short half-life may necessitate another dose after only 1 hour. The addition of naltrexone, another µ receptor antagonist which has a reported half-life of approximately 4 hours after oral administration, may extend its effectiveness. In a Phase 1 pharmacokinetic study, healthy adults were administered IN naloxone and naltrexone separately and in combination. When administered together, the Cmax of naltrexone decreased 61% and AUC0-inf decreased 32% compared to when it was given separately; lower concentrations of naltrexone were observed as early as 5 minutes post-dose. By contrast, the Cmax and AUC0-inf of naloxone decreased only 18% and 16%, respectively. This apparent interaction was investigated further to determine if naloxone and naltrexone shared a cell membrane transporter. Neither compound was a substrate for OCT1, OCT2, OCT3, OCTN1, or OCTN2. There was no evidence of the involvement of a transmembrane transporter (efflux ratio < 2) when they were tested separately or in combination at concentrations of 10 and 500 µM using MDCKII cell monolayers at pH 7.4. The efflux ratios of naloxone and naltrexone increased to 6 or greater when the apical solution was pH 5.5, the approximate pH of the nasal cavity, but a there was no apparent interaction when the two compounds were co-incubated. The mechanism of the IN interaction is not understood at present; the goal is to have an easily administered opioid antagonist that is effective for a longer period of time.SIGNIFICANCE STATEMENT n/a