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 deaminase 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'-deoxycoformycin. 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.
Wu
Jim Zhen
JZ
Drug Discovery and Development, Valeant Pharmaceuticals International, Costa Mesa, CA, USA. jwu@valeant.com
Yeh
Li-Tain
LT
Lin
Chin-Chung
CC
Hong
Zhi
Z
D000243:Adenosine Deaminase / Q000378:metabolism*; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D015649:Pentostatin / Q000494:pharmacology*; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
D058892:Adenosine Deaminase Inhibitors; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011355:Prodrugs; D015649:Pentostatin; D012254:Ribavirin; D000243:Adenosine Deaminase; C026956:taribavirin