title: Role of site-specific binding to plasma albumin in drug availability to brain.
abstract: Many studies have reported greater drug uptake into brain than that predicted based upon existing models using the free fraction (f(u)) of drug in arterial serum. To explain this difference, circulating plasma proteins have been suggested to interact with capillary membrane in vivo to produce a conformational change that favors net drug dissociation and elevation of f(u). Albumin, the principal binding protein in plasma, has two main drug binding sites, Sudlow I and II. We tested this hypothesis using drugs that bind selectively to either site I (warfarin) or site II (ibuprofen), as well as mixed ligands that have affinity for both sites (tolbutamide and valproate). Brain uptake was determined in the presence and absence of albumin using the in situ rat brain perfusion technique. Unidirectional brain uptake transfer constants (K(in)) were measured and compared with those predicted using the modified Kety-Crone-Renkin model: K(in) = F(1-e(-f(u) x PS(u)/F)), where F is perfusion flow and PS(u) is the permeability-surface area product to free drug of brain capillaries. The results demonstrated good agreement between measured and predicted K(in) over a 100-fold range in perfusion fluid albumin concentration using albumin from three different species (i.e., human, bovine, and rat), as well as whole-rat serum. K(in) decreased in the presence of albumin in direct proportion to perfusion fluid f(u) with constant PS(u). The results show that brain uptake of selected Sudlow site I and II ligands matches that predicted by the modified Kety-Crone-Renkin model with no evidence for enhanced dissociation.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter, Amarillo, TX 79106, USA.
authors.forename: Haritha
authors.initials: H
authors.lastname: Mandula
authors.forename: Jagan Mohan R
authors.initials: JM
authors.lastname: Parepally
authors.forename: Rose
authors.initials: R
authors.lastname: Feng
authors.forename: Quentin R
authors.initials: QR
authors.lastname: Smith
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D007052:Ibuprofen / Q000493:pharmacokinetics; D008297:Male; D010477:Perfusion; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000378:metabolism*; D014044:Tolbutamide / Q000493:pharmacokinetics; D014462:Ultrafiltration; D014635:Valproic Acid / Q000493:pharmacokinetics; D014859:Warfarin / Q000493:pharmacokinetics
chemical_list: D004364:Pharmaceutical Preparations; D012709:Serum Albumin; D014859:Warfarin; D014635:Valproic Acid; D014044:Tolbutamide; D007052:Ibuprofen