Pharmacokinetics of 3′-azido-2′,3′-dideoxy-5-methylcytidine in Rats

Abstract

3'-Azido-2',3'-dideoxy-5-methylcytidine (AzddMeC) has been shown to have potent activity against human immunodeficiency virus (HIV) in vitro. The purpose of this study was to characterize the pharmacokinetics of AzddMeC in rats. AzddMeC was administered intravenously at doses of 10, 50 and 100mg kg-\ Plasma and urine AzddMeC concentrations were determined by HPLC. Pharmacokinetic parameters were generated by area/moment analysis. Plasma AzddMeC concentrations after 10mg kg-1 were too low to accurately calculate pharmacokinetic parameters. Following 50 and 100mg kg-1 AzddMeC, plasma drug concentrations declined rapidly with a terminal half-life of approximately 2.5 h. No statistically significant differences were noted in pharmacokinetic parameters between the two higher doses. Total clearance was 1.57 ± 0.33 (mean ± SO) and 1.76 ± 0.321 h-1 kg-1 after 50 and 100mg kg-1 AzddMeC, respectively. Renal excretion accounted for approximately half of total clearance with 55 ± 11% of the dose recovered as unchanged drug in urine. AzddMeC was not metabolized by deamination to AZT in the rat. No glucuronide metabolite was found in urine. Steadystate volume of distribution of AzddMeC averaged 1.73 ± 0.78 and 1.46 ± 0.441 kg-1 following 50 and 100mg kg-\ respectively. Thus, the disposition of AzddMeC in rats is independent of dose over the range of 50-1 00 mg kg-1 • The pharmacokinetics of AzddMeC in rats are similar to those of 2',3'-dideoxycytidine, while the clearance of AzddMeC is 40% less than that of 3'-azido-3'-deoxythymidine.

Antiviral Activity and Pharmacokinetics of 1-(2,3-Dideoxy-2-Fluoro-β- l -Glyceropent-2-Enofuranosyl)Cytosine

“…The EC 50 and EC 90 values of the compound against the virus were 0.12 and 1.60 M, respectively, for HIV and 0.002 and 0.05 M, respectively, for HBV. Antiviral nucleosides generally demonstrate longer t 1/2 s in humans than in monkeys; e.g., the t 1/2 of 3TC is 1.40 h in monkeys versus 5 to 7 h in humans (1,3,23). However, the biological activity of nucleoside reverse transcriptase inhibitors (NRTIs) is due to the accumulation of intracellular nucleoside triphosphate (NRTI-TP).…”

“…1) (3,25,27). The t 1/2 s in plasma of these latter nucleosides range from 0.81 to 1.82 h. However the t 1/2 s of L-2Ј-Fd4C and D-D4FC are 5.02 and 3.57 h, respectively, suggesting that they may be given with a longer dose interval (22).…”

Pharmacokinetics of the Anti-Human Immunodeficiency Virus Agent 1-(β-d-Dioxolane)Thymine in Rhesus Monkeys

“…The animals were monitored for alertness, and additional anesthetics (30 to 60 mg of ketamine HCl) were administered as required. Blood samples were collected through the femoral vein at 0, 0.25, 0.5, 1, 1.5, 2, 3, 4,6,8,12, and 24 h after dosing. Cerebrospinal fluid (CSF) samples were collected from treated monkeys at 1 and 2 h after drug administration by a cisternal or lumbar tap using a 22-gauge needle.…”

“…The toxicities of AZT and D4T in humans undergoing treatment with these drugs are well known despite their usefulness in drug cocktails (1,23,33,36,37,42). Therefore, there is a need to develop TK-dependent nucleoside analogues with limited toxicities that could provide additional treatment options.The objective of this study was to assess the single-dose pharmacokinetics (PK) of D-DOT in rhesus monkeys given 33.3-mg/kg-of-body-weight intravenous and oral doses and to compare the pharmacokinetics with those of other structurally related antiretroviral nucleoside analogs that were previously administered to rhesus monkeys (7,8,10,11,12,24,28,30,34,39). …”

“…The objective of this study was to assess the single-dose pharmacokinetics (PK) of D-DOT in rhesus monkeys given 33.3-mg/kg-of-body-weight intravenous and oral doses and to compare the pharmacokinetics with those of other structurally related antiretroviral nucleoside analogs that were previously administered to rhesus monkeys (7,8,10,11,12,24,28,30,34,39).…”