title: Modulation of the partition coefficient between octanol and buffer at pH 7.4 and pKa to achieve the optimum balance of blood clearance and volume of distribution for a series of tetrahydropyran histamine type 3 receptor antagonists.
abstract: The relationship between rat pharmacokinetics and physicochemical parameters [the partition coefficient between octanol and buffer at pH 7.4 (log D((7.4))) and pK(a)] was studied for a series of tetrahydropyran compounds. Sixteen compounds ranging in log D((7.4)) 0.1 to 1.8 were administered intravenously to rats, and the pharmacokinetic parameters were determined from blood concentration time curves. Across the series, a weak correlation was observed between log D((7.4)) and blood clearance, suggesting that log D((7.4)) values less than 0.5 were required to prevent clearance at hepatic blood flow. In terms of the volume of distribution (V(d)), the compounds fell into three distinct subseries characterized by the number of basic centers and differences in ionization of each basic center at physiological pH. These were referred to as the monobasic, weak second base, and strong second base subseries. All the compounds exhibited V(d) greater than body water, as would be expected from their lipophilic and basic nature. For a given clog P, the strong second base subseries showed higher V(d) than the weak second base subseries, which in turn exhibited higher values than the monobasic subseries. In addition, for the weak second base subseries, V(d) could be tuned by modulating the pK(a) of the second basic center. This relationship was rationalized in respect to the interactions of the ionizable centers with phospholipid heads in the cell membrane and/or lysosomal trapping. Compounds in the weak second base subseries showed optimal V(d), and when combined with a log D((7.4)) of 0.1, driving to moderate blood clearance, one compound showed the optimal pharmacokinetic profile.
authors: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK. tanya.hay@pfizer.com
authors: Tanya
authors: T
authors: Hay
authors: Rhys
authors: R
authors: Jones
authors: Kevin
authors: K
authors: Beaumont
authors: Mark
authors: M
authors: Kemp
mesh_terms: D000818:Animals; D001682:Biological Availability; D002021:Buffers; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006207:Half-Life; D054828:Histamine H3 Antagonists / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver; D000442:Octanols / Q000737:chemistry*; D011485:Protein Binding; D011714:Pyrans / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002021:Buffers; D054828:Histamine H3 Antagonists; D000442:Octanols; D011714:Pyrans; D003577:Cytochrome P-450 Enzyme System