Conversion of Viramidine to Ribavirin in Vivo by Adenosine Deaminase and its Inhibition by 2′-Deoxycoformycin

Previously we reported that viramidine is a prodrug of ribavirin and that adenosine deami-nase catalyses viramidine deamination to ribavirin in vivo. This in vivo study explores this prodrug conversion in rats and inhibition by a potent adenosine deaminase inhibitor, 2′-deoxyco-formycin. We found that conversion of viramidine to ribavirin was viramidine dose-dependent in rat plasma. A single intravenous dose of 0.25 mg/kg 2′-deoxycoformycin suppressed orally administered viramidine conversion to ribavirin in plasma by 50%. The inhibition was 2′-deoxycoformycin dose-dependent and a single dose of 2 mg/kg decreased the ribavirin/viramidine area under the concentration—time curve between 0 h and 6 h ratio by 2.5-fold. These findings provide strong evidence that adenosine deaminase plays a major role in converting viramidine to ribavirin in vivo.