Open AccessPharmacokinetic characteristics of L ‐valyl‐ara‐C and its implication on the oral delivery of ara‐C 3
Author(s) -
CHEON Eunpa,
HAN Hyokyung
Publication year - 2007
Publication title -
acta pharmacologica sinica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.514
H-Index - 90
eISSN - 1745-7254
pISSN - 1671-4083
DOI - 10.1111/j.1745-7254.2007.00474.x
Subject(s) - prodrug , bioavailability , pharmacokinetics , chemistry , pharmacology , oral administration , in vitro , amide , stereochemistry , biochemistry , medicine
Aim: To evaluate the pharmacokinetic characteristics of L ‐valyl‐ara‐C, a peptidomimetic prodrug of ara‐C. Methods : After the synthesis of L ‐valyl‐ara‐C, the in vitro stability of L ‐valyl‐ara‐C was examined in various biological media. Plasma pharmacokinetic profiles of ara‐C and L ‐valyl‐ara‐C were also evaluated in rats. Results : The degradation of L ‐valyl‐ara‐C was negligible in fresh plasma and also in the presence of plasmin over a 2 h incubation period. Furthermore, L ‐valyl‐ara‐C appeared to be stable in the leukemia cell homogenates, and subsequently, it was far less cytotoxic than the parent, ara‐C in AML2 and L1210 cells. The chemical hydrolysis of L ‐valyl‐ara‐C was rather accelerated in acidic pH. Following an oral administration of L ‐valyl‐ara‐C, the appearance of ara‐C was observed in plasma although the systemic exposure of the prodrug was much higher than that of ara‐C. The bioavailability of ara‐C was about 4% via prodrug administration. Conclusion : The amide bond of L ‐valyl‐ara‐C was stable against the enzymatic hydrolysis, and the utility of L ‐valyl‐ara‐C as an oral delivery system of ara‐C appeared to be limited by its low metabolic conversion to ara‐C in rats.