title: Development of a Rat Plasma and Brain Extracellular Fluid Pharmacokinetic Model for Bupropion and Hydroxybupropion Based on Microdialysis Sampling, and Application to Predict Human Brain Concentrations.
abstract: Administration of bupropion [(±)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one] and its preformed active metabolite, hydroxybupropion [(±)-1-(3-chlorophenyl)-2-[(1-hydroxy-2-methyl-2-propanyl)amino]-1-propanone], to rats with measurement of unbound concentrations by quantitative microdialysis sampling of plasma and brain extracellular fluid was used to develop a compartmental pharmacokinetics model to describe the blood-brain barrier transport of both substances. The population model revealed rapid equilibration of both entities across the blood-brain barrier, with resultant steady-state brain extracellular fluid/plasma unbound concentration ratio estimates of 1.9 and 1.7 for bupropion and hydroxybupropion, respectively, which is thus indicative of a net uptake asymmetry. An overshoot of the brain extracellular fluid/plasma unbound concentration ratio at early time points was observed with bupropion; this was modeled as a time-dependent uptake clearance of the drug across the blood-brain barrier. Translation of the model was used to predict bupropion and hydroxybupropion exposure in human brain extracellular fluid after twice-daily administration of 150 mg bupropion. Predicted concentrations indicate that preferential inhibition of the dopamine and norepinephrine transporters by the metabolite, with little to no contribution by bupropion, would be expected at this therapeutic dose. Therefore, these results extend nuclear imaging studies on dopamine transporter occupancy and suggest that inhibition of both transporters contributes significantly to bupropion's therapeutic efficacy.
authors.affiliation: Brains On-Line BV, Groningen, The Netherlands (T.I.F.H.C., G.F. J.H.A.F.); Rollema Biomedical Consulting, Mystic, Connecticut (H.R.); and Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania (R.E.S.).
authors.forename: Thomas I F H
authors.initials: TI
authors.lastname: Cremers
authors.affiliation: Brains On-Line BV, Groningen, The Netherlands (T.I.F.H.C., G.F. J.H.A.F.); Rollema Biomedical Consulting, Mystic, Connecticut (H.R.); and Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania (R.E.S.).
authors.forename: Gunnar
authors.initials: G
authors.lastname: Flik
authors.affiliation: Brains On-Line BV, Groningen, The Netherlands (T.I.F.H.C., G.F. J.H.A.F.); Rollema Biomedical Consulting, Mystic, Connecticut (H.R.); and Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania (R.E.S.).
authors.forename: Joost H A
authors.initials: JH
authors.lastname: Folgering
authors.affiliation: Brains On-Line BV, Groningen, The Netherlands (T.I.F.H.C., G.F. J.H.A.F.); Rollema Biomedical Consulting, Mystic, Connecticut (H.R.); and Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania (R.E.S.).
authors.forename: Hans
authors.initials: H
authors.lastname: Rollema
authors.affiliation: Brains On-Line BV, Groningen, The Netherlands (T.I.F.H.C., G.F. J.H.A.F.); Rollema Biomedical Consulting, Mystic, Connecticut (H.R.); and Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania (R.E.S.) stratfordr@duq.edu.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stratford
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D016642:Bupropion / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism*; D006801:Humans; D008297:Male; D017551:Microdialysis / Q000379:methods; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D010949:Plasma / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C580748:hydroxybupropion; D016642:Bupropion