Abstract
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.
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Project supported by the Basic Research Program of Korea Science and Engineering Foundation (KOSEF) (No R012004000-1001302005).
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Cheon, Ep., Han, Hk. Pharmacokinetic characteristics of L-valyl-ara-C and its implication on the oral delivery of ara-C. Acta Pharmacol Sin 28, 268–272 (2007). https://doi.org/10.1111/j.1745-7254.2007.00474.x
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DOI: https://doi.org/10.1111/j.1745-7254.2007.00474.x
