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Enhanced Oral Bioavailability of DDI After Administration of 6-Cl-ddP, an Adenosine Deaminase-Activated Prodrug, to Chronically Catheterized Rats (1995)

Anderson, Bradley D. ; Morgan, Michael E. ; Singhal, Dharmendra

Springer

Pharmaceutical research 12 (1995), S. 1126-1133

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ISSN: 1573-904X

Keywords: oral ; portal ; bioavailability ; adenosine deaminase ; prodrugs ; dideoxyinosine

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. 6-Cl-2′,3′-dideoxypurine (6-Cl-ddP), an adenosine deaminase (ADA) activated prodrug of ddI, may be an effective antiretroviral agent for the treatment of AIDS dementia due to its ability to deliver increased concentrations of ddI to brain tissue. To examine the feasibility of administering this drug orally, the oral and hepatic portal bioavailabilities of 6-Cl-ddP were determined. In addition, the oral and portal bioavailabilities of ddI after administration of the prodrug were compared to those from administration of ddI itself. Methods. Pharmacokinetic and bioavailability studies were conducted in fully conscious, chronically catheterized rats in a randomized crossover design. Plasma ddI and 6-Cl-ddP concentration-time profiles were determined by HPLC. Results. 6-Cl-ddP has poor apparent oral bioavailability (7% ± 3%, n = 3) but high bioavailability after portal administration (97% ± 11%), suggesting either poor absorption or extensive gut wall metabolism. The appearance of 〉50% of the dose as ddI in the systemic circulation after an oral dose of 6-Cl-ddP rules out poor absorption of the prodrug, and confirms expectations of high ADA activity in the gastrointestinal tract. Gastric administration of 6-Cl-ddP resulted in a 〉 10-fold increase in the oral bioavailability of ddI, from 3–7% to 〉50%, and a significant decrease in the variability in apparent bioavailability. Conclusions. These data indicate that lipophilic adenosine deaminase activated prodrugs of dideoxypurine nucleosides may have limited utility for improving CNS delivery after oral administration but may be useful in enhancing the oral bioavailability of highly polar and therefore poorly absorbed dideoxynucleosides.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1016299507382

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Role of Brain Tissue Localized Purine Metabolizing Enzymes in the Central Nervous System Delivery of Anti-HIV Agents 2′-β-Fluoro-2,3′-Dideoxyinosine and 2′-β-Fluoro-2′,3′-Dideoxyadenosine in Rats (1997)

Singhal, Dharmendra ; Morgan, Michael E. ; Anderson, Bradley D.

Springer

Pharmaceutical research 14 (1997), S. 786-792

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ISSN: 1573-904X

Keywords: dideoxyadenosine ; blood-brain barrier ; adenosine deaminase ; purine nucleoside phosphorylase ; inhibitor

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. This study examines the central nervous system (CNS) delivery of 2′-β-fluoro-2′,3′-dideoxyadenosine (F-ddA) and 2′-β-fluoro-2′,3′-dideoxyinosine (F-ddl), acid stable analogues of dideoxyadenosine (ddA) and dideoxyinosine (ddI) having reduced susceptibility to purine salvage pathway enzymes important in the metabolism of ddA and ddI, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), respectively. Their CNS delivery compared to that for ddI provides insight into the role of brain tissue ADA and PNP in these processes. Methods. Brain and cerebrospinal fluid (CSF) concentration-time profiles were obtained for F-ddI during and after intravenous infusions of F-ddl, and for both F-ddA and F-ddI after F-ddA infusions in normal rats or rats pre-treated with the ADA inhibitor 2′-deoxycoformycin (DCF). Rate constants for CNS entry, efflux and metabolism were estimated by computer fits using plasma concentration-time profiles as the driving force functions. Results. The CNS delivery of F-ddI did not differ significantly from that for ddI. F-ddA, which is more lipophilic than F-ddI, provided higher brain (≈ 8×) and CSF (≈ 11×) concentrations of total dideoxynucleoside (F-ddA and F-ddI) compared to F-ddI. Deamination by brain tissue ADA to form F-ddI reduced CNS levels of intact F-ddA but provided higher brain parenchyma (5×) and CSF/plasma (3×) ratios of F-ddI relative to F-ddI controls. Thus, F-ddA functions in part as a CNS-activated prodrug of F-ddI. DCF pre-treatment inhibited brain tissue ADA, abolishing the prodrug effect, and enhancing F-ddA concentrations in both brain parenchyma (5×) and CSF (6×). Conclusions. PNP metabolism does not appear to play a role in the low CNS delivery of ddI. On the other hand, deamination of F-ddA by brain tissue ADA is an important process, such that F-ddA functions in part as a CNS-activated prodrug of F-ddI. Enhanced CNS uptake of intact F-ddA can be achieved with ADA inhibition.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1012110724604

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