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

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.

journal_name

Acta Pharmacol Sin

authors

Cheon EP,Han HK

doi

10.1111/j.1745-7254.2007.00474.x

subject

Has Abstract

pub_date

2007-02-01 00:00:00

pages

268-72

issue

2

eissn

1671-4083

issn

1745-7254

journal_volume

28

pub_type

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