This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.b-D-Dioxolane-2,6-diaminopurine (DAPD) is the prodrug of b-D-dioxolane guanosine (DXG) that is readily converted into DXG by the ubiquitous enzyme adenosine deaminase. DXG has potent, selective in vitro activity against several clinically important resistant HIV mutants and is in advanced preclinical development. Average oral bioavailability of DAPD/DXG after DAPD oral administration was only 30% in rhesus monkeys. Valyl-(-)-b-D-2,6-diaminopurine dioxolane (Val-DAPD), a prodrug of DAPD was synthesized in an effort to improve oral bioavailability. Single dose oral pharmacokinetics of Val-DAPD was studied in 3 rhesus monkeys. Urine and serum samples were collected after dosing at 8 and 24 h, respectively. Cerebrospinal fluid (CSF) samples were collected at 1, 2 and 3 h. A non-compartmental pharmacokinetic analysis was performed to the serum data using a non-linear regression curve-fitting program (WinNonlin). A large variation in the pharmacokinetic (PK) parameters was found in the monkeys following 33.3 mg/kg val-DAPD oral administration. Peak serum concentrations were achieved between 0.25 to 3 h (Tmax) after dosing. Terminal half-lives for DXG were between 0.58 to 2.83 h. Volumes of distribution/F ranged from 2.37 to 16.33 l/kg; the average oral systemic clearance/F value was 7.9 l/kg/h. DXG was found in the CSF samples except in one monkey due to the time-lag (tlag) of 2 h and 3 h samples not collected from this animal. Three, 11 and 23% of the administered dose was recovered in the form of DAPD and 14, 19 and 35% was recovered in the form of DXG in the urine, within 8 h of administration. A total of 17, 30, and 58% of the administered dose were eliminated within 8 h in the urine, suggesting that the prodrug was rapidly hydrolyzed into DAPD and gave reasonably high levels of DXG in two animals. Very low absorption was noted in one animal. Further work is needed to identify sources of inter-individual pharmacokinetic variability.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000165-47
Application #
7562495
Study Section
Special Emphasis Panel (ZRR1-CM-8 (01))
Project Start
2007-05-01
Project End
2008-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
47
Fiscal Year
2007
Total Cost
$78,544
Indirect Cost
Name
Emory University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Robinson, Amy A; Abraham, Carmela R; Rosene, Douglas L (2018) Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys. Geroscience 40:31-47
Walker, Lary C (2018) Sabotage by the brain's supporting cells helps fuel neurodegeneration. Nature 557:499-500
Mascaro, Jennifer S; Rentscher, Kelly E; Hackett, Patrick D et al. (2018) Preliminary evidence that androgen signaling is correlated with men's everyday language. Am J Hum Biol 30:e23136
Forger, Nancy G; Ruszkowski, Elara; Jacobs, Andrew et al. (2018) Effects of sex and prenatal androgen manipulations on Onuf's nucleus of rhesus macaques. Horm Behav 100:39-46
Claw, Katrina G; George, Renee D; MacCoss, Michael J et al. (2018) Quantitative evolutionary proteomics of seminal fluid from primates with different mating systems. BMC Genomics 19:488
Adekambi, Toidi; Ibegbu, Chris C; Cagle, Stephanie et al. (2018) High Frequencies of Caspase-3 Expressing Mycobacterium tuberculosis-Specific CD4+ T Cells Are Associated With Active Tuberculosis. Front Immunol 9:1481
Beck, Goichi; Maehara, Shunsuke; Chang, Phat Ly et al. (2018) A Selective Phosphodiesterase 10A Inhibitor Reduces L-Dopa-Induced Dyskinesias in Parkinsonian Monkeys. Mov Disord 33:805-814
Georgieva, Maria; Sia, Jonathan Kevin; Bizzell, Erica et al. (2018) Mycobacterium tuberculosis GroEL2 Modulates Dendritic Cell Responses. Infect Immun 86:
Tedesco, Dana; Grakoui, Arash (2018) Environmental peer pressure: CD4+ T cell help in tolerance and transplantation. Liver Transpl 24:89-97
Mavigner, Maud; Habib, Jakob; Deleage, Claire et al. (2018) Simian Immunodeficiency Virus Persistence in Cellular and Anatomic Reservoirs in Antiretroviral Therapy-Suppressed Infant Rhesus Macaques. J Virol 92:

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