Thymidine 5'-O-pivaloate: evidence for prodrug action in the rat and rhesus monkey

Thymidine (TdR) 5'-O-pivaloate was administered to rats and a rhesus monkey to assess its prodrug characteristics. Within 15 minutes after a 2000-mg/kg oral or sc bolus in rats, free TdR was detected in the serum of liquid chromatography. At 1 hour the TdR level reached a plateau of approximately 0.6 mM with oral administration and 0.1 mM with sc treatment. In the monkey experiment, radioactivity was detected in the serum 15 minutes after oral administration of 200 mg/kg of [3H]TdR 5'-O-pivaloate. Thin-layer chromatographic analysis showed that this consisted of unchanged ester as well as free TdR and thymine. The concentration of intact ester reached a peak value of 5.4 microM after 40 minutes, before declining to a steady level of 0.9--1.0 microM over the next 6 hours. Serum [3H]TdR and [3H]thymine followed a similar course, except that both remained in the range of 1.0--1.2 microM for as long as 24 hours. Total recovery of radioactivity in the urine over the first 6 hours was 2.5% of the administered dose, will all compounds present in equal proportions. The results of these studies are consistent with absorption of intact pivaloate ester from the stomach, followed by gradual cleavage to TdR and catabolism of TdR to thymine and subsequent products. With a single oral dose of ester, it was possible to achieve, and maintain for up to 24 hours, a level (1 microM) of free TdR in the serum which has previously been found to protect normal tissues during high-dose methotrexate therapy.