Stability and perfusion studies of Desmopressin (dDAVP) and prodrugs in the rat jejunum

Citation
Ei. Lepist et al., Stability and perfusion studies of Desmopressin (dDAVP) and prodrugs in the rat jejunum, EXP TOX PAT, 51(4-5), 1999, pp. 363-368
Citations number
17
Categorie Soggetti
Pharmacology & Toxicology
Journal title
EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY
ISSN journal
09402993 → ACNP
Volume
51
Issue
4-5
Year of publication
1999
Pages
363 - 368
Database
ISI
SICI code
0940-2993(199907)51:4-5<363:SAPSOD>2.0.ZU;2-Z
Abstract
Three aliphatic carboxylic acid esters of the tyrosine phenolic group in De smopressin (dDAVP) were investigated in vitro for their stability and metab olism in rat gastrointestinal media. The degradation followed strictly firs t-order kinetics and the prodrugs were quantitatively converted to dDAVP. T he n-hexanoyl (II) and n-octanoyl (III) esters were rapidly hydrolysed in 1 0 % rat jejunal fluid showing half-lives of 1.1 +/- 0.2 min and 1.4 +/- 0.1 min, respectively. In 5 % rat jejunal homogenate the half-lives were 3.2 /- 0.2 min and < 30 sec, respectively. The sterically hindered pivalate est er (I) proved to be more stable. The half-lives were 10.3 +/- 0.3 min in 10 % rat jejunal fluid and 1.5 +/- 0.1 min in 10 % rat jejunal homogenate, re spectively. The presence of paraoxon, an inhibitor of type B esterases sign ificantly decreased the degradation rate of the pivalate ester (I) in rat j ejunal fluid (t(1/2) > 5 hrs) indicating that the prodrug is converted to d DAVP by rapid luminal breakdown of the ester bond. It was shown that approx imately 13 % of prodrug I disappeared from the gut lumen during a single-pa ss perfusion experiment in rat jejunum. Our results indicate that the disap pearence from the jejunal lumen was primarily caused by degradation of the prodrug to dDAVP by esterases rather than absorption. The better stability of the sterically hindrered prodrug (I) indicate that even more sterically hindered prodrugs will be a better choice for a further optimization of sta bility and lipophilicity, and consequently a potentially improved intestina l absorption of dDAVP.