Pharmacokinetics of 2',3'-dideoxyinosine in monkeys

Abstract

Comparison of the pharmacokinetic parameters obtained for dideoxyinosine (ddl) in monkeys with those obtained for humans indicates that the monkey is an appropriate animal model for ddl pharmacokinetics in humans. Following intravenous administration of 20 mg of ddI per kg of body weight and measurement of ddl in plasma and urine by high-performance liquid chromatography, pharmacokinetic parameters were determined by noncompartmental analysis. Total systemic clearance was 0.74 liters/h/kg, volume of distribution was 0.92 liters/kg, and the elimination half-life of ddI was 1.22 h. The pharmacokinetics of ddl in five monkeys were determined following intravenous administration of 20 mg/kg and were found to be comparable to those obtained in patients with AIDS.2',3'-Dideoxyinosine (ddl) is a purine nucleoside analog that suppresses the infectivity and the cytopathic effect of human immunodeficiency virus in vitro (8). Intracellular 5'-triphosphate metabolites of ddl mediate anti-human immunodeficiency virus activity by inhibition of viral reverse transcriptase and by their incorporation into DNA chains, resulting in chain termination (3,8). The favorable in vitro activity-toxicity profile of ddl, as well as its long intracellular half-life of more than 12 h (1), has prompted a number of clinical trials of ddI as a potential anti-AIDS drug.Pharmacokinetic studies of ddl have been completed in mice (11), in rats (2, 9), and in patients with AIDS (4,5,7,12). Total systemic clearance and the elimination half-life in rodents were different from those in humans (elimination half-life ranged from 5 to 28 min in rodents and ranged from 38 min to 1.6 h in humans). The fractional urinary elimination and renal clearance of ddl have been reported in humans (7) but not in animals. Thus, at present there is not an abundance of pharmacokinetic data for ddl in animals, and of the species studied none appear to be suitable animal models for ddl pharmacokinetics in humans. Characterization of the pharmacokinetics of ddl in animals and hopefully, identification of an appropriate animal model will be useful in designing future studies, such as pharmacokinetic evaluations of drug interactions between anti-human immunodeficiency virus nucleosides. The current investigation was undertaken to determine the pharmacokinetics of ddl and to determine in what capacity monkeys would serve as an animal model for ddl pharmacokinetics. Five adult male monkeys (Macaca fascicularis), each weighing from 4.09 to 5.34 kg, were used for the pharmacokinetic study, after receiving approval from the University of Georgia Animal Care and Use Committee. Each animal was administered 20 mg of ddl prepared in sterile normal saline per kg of body weight intravenously (i.v.) into a leg vein over 1 min. For ddI administration and at blood collection times, animals were transferred to a device that provided access to the leg vein without anesthesia. Immediately following dosing, each animal was placed in a metabolism cage to facilitate

Pharmacokinetics and metabolism of racemic 2',3'-dideoxy-5-fluoro-3'-thiacytidine in rhesus monkeys

“…In summary, the pharmacokinetics of FTC in rhesus monkeys were, in general, similar to those of other anti-HIV-1 nucleosides (2,15,19,23,25 (11,24,27). The finding that the L-(-)-form of FTC is a more potent and less toxic enantiomer against HIV and HBV in cell culture and is also more resistant to deamination suggests that this compound should be further evaluated instead of racemic FTC or (+)-FTC.…”

“…The ratios of transaminase,'and lactate dehydrogenase during the first 24 h nucleoside concentrations in CSF-serum for FTC and FTU following drug administration. Since comparable elevations (2,15,19,23). Thus, the rhesus monkey appears to be an excellent animal model for examining the pharmacokinetics of nucleoside analogs.…”

Pharmacokinetics of the anti-human immunodeficiency virus nucleoside analog stavudine in cynomolgus monkeys

“…Of the animals investigated, the monkey has been identified as an appropriate animal model for zidovudine pharmacokinetics in humans (3,5,10,11,18) compared with other animals (11,18,19,37). Likewise, the monkey appears to be an acceptable model for didanosine pharmacokinetics in humans (33).…”

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

“…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).…”

“…The monkeys were given 33.3 mg of L-2Ј-Fd4C per kg of body weight i.v. (in 10 ml of PBS) so that comparisons could be made with results of previously reported studies (1,22,25,28). A washout period of at least 4 weeks was used between doses.…”