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 pKa] 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 (Vd), 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 Vd 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 Vd than the weak second base subseries, which in turn exhibited higher values than the monobasic subseries. In addition, for the weak second base subseries, Vd could be tuned by modulating the pKa 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 Vd, and when combined with a log D(7.4) of 0.1, driving to moderate blood clearance, one compound showed the optimal pharmacokinetic profile.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.109.027888.
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ABBREVIATIONS: THP, tetrahydropyran; H3, histamine type 3 receptor; log P, the partition coefficient of a compound between octanol and water in its un-ionized form; HPLC, high-performance liquid chromatography; log D(7.4), the partition coefficient between octanol and buffer at pH 7.4; AUC, area under the concentration versus time curve; Cl, clearance; Vd, volume of distribution; Vdu, unbound volume of distribution; Clu, unbound clearance.
- Accepted June 18, 2009.
- Received April 14, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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