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.