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.

• Authors: Eun-pa Cheon, Hyo-kyung Han
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 28 Issue 2 Pg. 268-72 (Feb 2007) ISSN: 1671-4083 [Print] United States
• PMID: 17241530 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• L-valyl-ara-C
• Prodrugs
• Cytarabine

Topics

• Administration, Oral
• Animals
• Cell Proliferation (drug effects)
• Cytarabine (administration & dosage, analogs & derivatives, chemistry, metabolism, pharmacokinetics)
• Drug Delivery Systems
• Drug Stability
• Hydrogen-Ion Concentration
• Leukemia L1210
• Male
• Prodrugs (pharmacokinetics)
• Rats
• Rats, Sprague-Dawley