Pharmacokinetic characteristics of L-valyl-ara-C and its implication on the oral delivery of ara-C.
OBJECTIVE
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.


CONCLUSIONS
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.
Cheon
Eun-pa
EP
College of Pharmacy, Chosun University, Gwangju 501-759, Korea.
Han
Hyo-kyung
HK
D000284:Administration, Oral; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007939:Leukemia L1210; D008297:Male; D011355:Prodrugs / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
C515249:L-valyl-ara-C; D011355:Prodrugs; D003561:Cytarabine