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.

Synthesis of n-squalenoyl cytarabine and evaluation of its affinity with phospholipid bilayers and monolayers

“…For example, l-valine was introduced at the NH 2 group of cytarabine to synthesize N4-l-valyl-Ara-C, but the oral bioavailability was only 4% after its oral administration in rats (Cheon et al, 2006;Cheon and Han, 2007). Similar results were obtained when the long-chain fatty acids were introduced at the 5 -hydroxyl of cytarabine (Gray et al, 1972).…”

Combination of l-Carnitine with Lipophilic Linkage-Donating Gemcitabine Derivatives as Intestinal Novel Organic Cation Transporter 2-Targeting Oral Prodrugs

“…In general, the ester bond is not very stable to enzymatic hydrolysis. 14 For example, 5′-O-L-phenylalanyl-decitabine is rapidly hydrolyzed in intestinal fluid, with a very short half-life (95 min). 15 In this study, OCTN2-targeting gemcitabine prodrugs showed excellent enzymatic stability, thereby reducing the extent of intestinal degradation to gemcitabine and increasing the targeting delivery efficiency, which is very consistent with the results of the previous study of the valproate amide prodrug of gemcitabine.…”

“…An ideal prodrug should exhibit excellent stability in the GI tract before interaction with OCTN2 and then must be converted to the parent drug in the systematic circulation. In general, the ester bond is not very stable to enzymatic hydrolysis . For example, 5′- O - l -phenylalanyl-decitabine is rapidly hydrolyzed in intestinal fluid, with a very short half-life (95 min) .…”

Transporter-targeted cholic acid-cytarabine conjugates for improved oral absorption

“…Among these prodrugs, L-valine-cytarabine has been synthesized in two ways using N 4 -L-valyl-cytarabine and 5'-L-valyl-cytarabine. The former had only a 4% oral bioavailability of cytarabine in rats due to the limited drug release from the prodrug (Cheon and Han, 2007). While the latter provided a 1.75-fold increased oral bioavailability of cytarabine with a suitable conversion rate in vivo.…”