title: Co-administration of a nanosuspension of a poorly soluble basic compound and a solution of a proton pump inhibitor--the importance of gastrointestinal pH and solubility for the in vivo exposure.
abstract: In Sigfridsson et al. (2011, Drug Dev Ind Pharm, 37:243-251), there was no difference in plasma concentration of BA99 when administering the drug as nanosuspension or microsuspension and analyzing the blood samples by liquid chromatography-mass spectrometry. This was related to the dissolved amount of drug in the gastric tract, which was high enough to support fast absorption when the drug reached the small intestine. One single physicochemical property (pK(a), about 3 for BA99) abolished the benefit of small particles. These results were further confirmed in the present study, where a proton pump inhibitor, AZD0865, was used to elevate the gastric pH and then drastically decreased the gastric solubility. In this way, BA99 could be considered as a model compound for a neutral substance. By increasing the gastric pH to 5-6 and 8-9, respectively, in rats, the plasma concentrations of BA99, after administering nanosuspensions, were unchanged compared with untreated (i.e. no AZD0865) animals. For microsuspensions of the test compound, on the other hand, the exposure of BA99 was 2- to 3-fold lower than for nanosuspensions at both pHs. Moreover, the blood concentrations of BA99 administered as microsuspension were also 2- to 3-fold lower compared with untreated (no AZD0865) individuals receiving both nanoparticles and microparticles of BA99. Obviously, for neutral compounds, with similar physicochemical properties as the present compound, size reduction will be crucial for increased plasma exposure. For basic compounds, with similar physicochemical properties as the present compound, the crucial step for absorption is the dissolution and solubility in the gastric tract.
authors.affiliation: Pharmaceutical Development, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden. carl-gustav.sigfridsson@astrazeneca.com
authors.forename: Kalle
authors.initials: K
authors.lastname: Sigfridsson
authors.forename: Anders
authors.initials: A
authors.lastname: Lundqvist
authors.forename: Marie
authors.initials: M
authors.lastname: Strimfors
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004338:Drug Combinations; D005260:Female; D005744:Gastric Acid / Q000737:chemistry*; D041981:Gastrointestinal Tract / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D054328:Proton Pump Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: C514958:AZD0865; D004338:Drug Combinations; D007093:Imidazoles; D054328:Proton Pump Inhibitors; D011725:Pyridines