On the bioavailability of oral and subcutaneous 2-chloro-2'-deoxyadenosine in humans: alternative routes of administration.

PURPOSE: The antimetabolite 2-chloro-2'-deoxyadenosine (CdA) is a promising alternative to alkylating agents for the treatment of lymphoproliferative disorders. Its use, however, is hampered by the need for intravenous (IV) administration. The aim of the present study was to determine the bioavailability of subcutaneously (SC) and orally administered CdA, and to establish an oral dose of CdA that could supersede IV administration. PATIENTS AND METHODS: A previously developed high-performance liquid chromatography method was used for the determination of plasma CdA concentrations in 13 patients. Ten patients were treated on alternate days with 0.14 mg/kg/d CdA as a 2-hour IV infusion or by a SC injection. Three of these patients were also given 0.14 mg/kg CdA orally in enteric-coated capsules. Ten patients were administered CdA orally that was dissolved in phosphate-buffered saline (PBS) after treatment with 20 mg omeprazole 1 and 6 hours before the administration of CdA.
RESULTS: The bioavailability of SC CdA was 102% +/- 28% (mean +/- SD), and the bioavailability of CdA administered in enteric-coated capsules was 19%, 24%, and 60%. In the three patients who were given 0.14 mg/kg orally dissolved in PBS, the bioavailability was 48% +/- 8%, whereas in the seven patients who received 0.28 mg/kg, the bioavailability was 55% +/- 17%. In the 10 patients who were treated with the CdA solution orally, the coefficients of variation of the areas under the curve (AUCs) after oral and IV administration were similar. Thus, oral administration did not add to the interindividual variability.
CONCLUSIONS: We conclude that orally administered CdA can supersede IV infusion if the dose is doubled. SC administration gives a high peak concentration of short duration with an AUC identical to that of IV infusion. Thus, SC injection can also be used as an alternative to IV infusion.