RT Journal Article
SR Electronic
T1 Absorption, Distribution, Metabolism, and Excretion Considerations in Selection of Orally Active Indole-Containing Endothelin Antagonist
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1424
OP 1431
VO 29
IS 11
A1 Donald K. Walker
A1 Kevin N. Dack
A1 Roger P. Dickinson
A1 Katherine S. Fenner
A1 Kim James
A1 David J. Rawson
A1 Dennis A. Smith
YR 2001
UL http://dmd.aspetjournals.org/content/29/11/1424.abstract
AB A series of potent indole-containing endothelin antagonists were evaluated in rat pharmacokinetic studies as part of a rational drug design program. Early compounds in this series were found to show poor gastrointestinal absorption, limiting their utility as oral agents. Structural modifications and pharmacokinetic studies indicated that reducing the overall H-bonding potential, through a reduction in the number of H-bond donors and acceptors, could increase absorption of the molecules. There was a correlation between calculated H-bonding capacity and rate of permeability across Caco-2 monolayers for this series of compounds. Caco-2 permeability was also shown to be indicative of the estimated extent of absorption in rats. Balancing the requirements of absorption and systemic clearance lead to the selection of an alcohol-containing compound, compound 7a (single enantiomer of compound 7) that was moderately absorbed after oral administration and converted to an active acid metabolite, which itself was of low intrinsic clearance. Species differences were observed between the absorption of compound 7a in rat and dog and also in the extent of conversion to the acid metabolite. Absorption was estimated at 30% in rat and 100% in dog. Approximately 30% of the absorbed drug was converted to systemically available acid metabolite in rat, compared with only 3% in dog. The American Society for Pharmacology and Experimental Therapeutics