The rate of dasotraline brain entry is slow following intravenous administration.
Rationale: Drugs that rapidly increase dopamine levels have an increased risk of abuse. Dasotraline (DAS) is a dopamine and norepinephrine reuptake inhibitor characterized by slow oral absorption with low potential for abuse. However, it remains unclear whether intravenous (i.v.) administration woul...
| Publicado en: | Psychopharmacology Vol. 237; no. 11; pp. 3435 - 3447 |
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| Autores principales: | , , , , , , , |
| Formato: | Journal Article |
| Publicado: |
Springer Nature
Nov2020
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=146477655&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 146477655 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00333158 EJD jtl: Psychopharmacology issn: 00333158 maglogo: N pubinfo: dt: Nov2020 vid: 237 iid: 11 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 146477655 145219663 10.1007/s00213-020-05623-8 146477655 ppf: 3435 ppct: 12 formats: fmt: @attributes: type: P tig: atl: The rate of dasotraline brain entry is slow following intravenous administration. aug: au: Lew, Robert Constantinescu, Cristian C. Holden, Daniel Carson, Richard E. Carroll, Vincent Galluppi, Gerald Koblan, Kenneth S. Hopkins, Seth C. affil: Sunovion Pharmaceuticals Inc., 84 Waterford Dr, 01752, Marlborough, MA, USA sug: ab: Rationale: Drugs that rapidly increase dopamine levels have an increased risk of abuse. Dasotraline (DAS) is a dopamine and norepinephrine reuptake inhibitor characterized by slow oral absorption with low potential for abuse. However, it remains unclear whether intravenous (i.v.) administration would facilitate the rapid elevation of dopamine levels associated with stimulant drugs. Objective: To assess the kinetics of DAS across the blood-brain barrier and time to onset of dopamine transporters (DAT) inhibition. Methods: We compared the onset of DAT occupancy and the associated elevation of synaptic dopamine levels in rhesus monkey following i.v. administration of DAS or methylphenidate (MPH) using positron emission tomography (PET). Brain entry times were estimated by reductions in [18F]-FE-PE2I binding to DAT in rhesus monkeys. Elevations of synaptic dopamine were estimated by reductions in [11C]-Raclopride binding to D2 receptors. Results: Intravenous administration of DAS (0.1 and 0.2 mg/kg) resulted in striatal DAT occupancies of 54% and 68%, respectively; i.v. administered MPH (0.1 and 0.5 mg/kg) achieved occupancies of 69% and 88% respectively. Brain entry times of DAS (22 and 15 min, respectively) were longer than for MPH (3 and 2 min). Elevations in synaptic dopamine were similar for both DAS and MPH however the time for half-maximal displacement by MPH (t = 23 min) was 4-fold more rapid than for DAS (t = 88 min). Conclusions: These results demonstrate that the pharmacodynamics effects of DAS on DAT occupancy and synaptic dopamine levels are more gradual in onset than those of MPH even with i.v. administration that is favored by recreational drug abusers. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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