TY - JOUR
T1 - 3′-Azido-2′,3′-Dideoxyuridine (AzddU)
T2 - Comparative Pharmacokinetics with 3′-Azido-3′-Deoxythymidine (AZT) in Monkeys
AU - Boudinot, F. Douglas
AU - Gallo, James M.
AU - Doshi, Kokila J.
AU - Schinazi, Raymond F.
AU - Mcclure, Harold M.
AU - Anderson, Daniel C.
AU - Kambhampathi, Pullaiah C.
AU - Chu, Chung K.
PY - 1990/2
Y1 - 1990/2
N2 - The pharmacokinetics of the anti-human immunodeficiency virus type 1 nucleosides, 3′-azido-2′,3′-dideoxyuridine (AzddU) and 3′-azido-3′-deoxythymidine (AZT) were characterized in rhesus monkeys. Half-life, total clearance, and steady-state volume of distribution were similar for both compounds. The observed pharmacokinetic parameters for AZT were comparable to those previously reported in humans. Oral absorption of AzddU and AZT was virtually complete after 60 mg/kg. However, bioavailability of both nucleosides was markedly lower (<50%) after 200 mg/kg, possibly indicating the involvement of a saturable absorption mechanism. The nucleosides were also well absorbed after subcutaneous administration. AzddU and AZT penetrated the cerebrospinal fluid (CSF) with concentration ratios in CSF:serum ranging from 0.05 to 0.25 one hour after drug administration. The glucuronides of AZT and AzddU were readily detected in urine. Hemogram and blood chemistry values for animals receiving short-term treatment (3 doses) with either AZT or AzddU did not exhibit any significant changes when compared with untreated control monkeys. The similar pharmacokinetic characteristics of AzddU compared with AZT suggest that clinical trials of AzddU are warranted.
AB - The pharmacokinetics of the anti-human immunodeficiency virus type 1 nucleosides, 3′-azido-2′,3′-dideoxyuridine (AzddU) and 3′-azido-3′-deoxythymidine (AZT) were characterized in rhesus monkeys. Half-life, total clearance, and steady-state volume of distribution were similar for both compounds. The observed pharmacokinetic parameters for AZT were comparable to those previously reported in humans. Oral absorption of AzddU and AZT was virtually complete after 60 mg/kg. However, bioavailability of both nucleosides was markedly lower (<50%) after 200 mg/kg, possibly indicating the involvement of a saturable absorption mechanism. The nucleosides were also well absorbed after subcutaneous administration. AzddU and AZT penetrated the cerebrospinal fluid (CSF) with concentration ratios in CSF:serum ranging from 0.05 to 0.25 one hour after drug administration. The glucuronides of AZT and AzddU were readily detected in urine. Hemogram and blood chemistry values for animals receiving short-term treatment (3 doses) with either AZT or AzddU did not exhibit any significant changes when compared with untreated control monkeys. The similar pharmacokinetic characteristics of AzddU compared with AZT suggest that clinical trials of AzddU are warranted.
UR - http://www.scopus.com/inward/record.url?scp=0025238727&partnerID=8YFLogxK
U2 - 10.1089/aid.1990.6.219
DO - 10.1089/aid.1990.6.219
M3 - Article
C2 - 2328158
AN - SCOPUS:0025238727
SN - 0889-2229
VL - 6
SP - 219
EP - 228
JO - AIDS Research and Human Retroviruses
JF - AIDS Research and Human Retroviruses
IS - 2
ER -