Document Detail


Absorption and intestinal metabolism of purine dideoxynucleosides and an adenosine deaminase-activated prodrug of 2',3'-dideoxyinosine in the mesenteric vein cannulated rat ileum.
MedLine Citation:
PMID:  9572907     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
This study investigates the mechanisms of absorption and the role of intestinally localized purine salvage pathway enzymes on the ileal availabilities of 2',3'-dideoxyinosine (ddI), a substrate for purine nucleoside phosphorylase (PNP); 2'-fluoro-2',3'-dideoxyinosine (F-ddI), a non-PNP substrate; and 6-chloro-2',3'-dideoxypurine (6-Cl-ddP), an adenosine deaminase (ADA) activated prodrug of ddI. The potential for increasing the intestinal availability of 6-Cl-ddP through the use of ADA inhibitors, namely, 2'-deoxycoformycin (DCF) and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), is also explored. Drug permeability coefficients across the intestinal epithelium were determined in in situ perfusions in the mesenteric vein cannulated rat ileum based on both drug appearance in blood (Pblood) and disappearance from the lumen (Plumen) and their paracellular and transcellular components were estimated by comparison to the permeabilities of two paracellular markers, mannitol and urea. Values of Pblood for ddI were determined to be (1.1 +/- 0.3) x 10(-6) cm/s, in close agreement with the value of (1.0 +/- 0.3) x 10(-6) cm/s obtained for F-ddI, a PNP resistant analogue of ddI having virtually the same molecular size and lipophilicity as ddI. This indicates that PNP may not play an important role in the low intestinal absorption of ddI. The Pblood for 6-Cl-ddP, (19 +/- 2) x 10(-6) cm/s, was 4.5-fold lower than Plumen, (84 +/- 12) x 10(-6) cm/s, which means that 77 +/- 6% of 6-Cl-ddP was metabolized during its intestinal transport, thus qualitatively accounting for the low oral bioavailability (7%) of 6-Cl-ddP observed in vivo in rats. Extensive intracellular metabolism of 6-Cl-ddP by ADA was confirmed by the high concentrations of ddI found both in the intestinal lumen and blood during 6-Cl-ddP perfusions and by a rate of ddI appearance in blood which was approximately 10-fold higher than ddI controls. Co-perfusion of the potent, hydrophilic ADA inhibitor DCF (Ki = 0. 001-0.05 nM) with 6-Cl-ddP led to only partial inhibition of intestinal ADA, while complete inhibition was obtained using the less potent but more lipophilic inhibitor EHNA (Ki = 1-20 nM). Hence, EHNA may be used to improve intestinal absorption of 6-Cl-ddP in vivo.
Authors:
D Singhal; N F Ho; B D Anderson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  87     ISSN:  0022-3549     ISO Abbreviation:  J Pharm Sci     Publication Date:  1998 May 
Date Detail:
Created Date:  1998-06-24     Completed Date:  1998-06-24     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985195R     Medline TA:  J Pharm Sci     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  569-77     Citation Subset:  IM; X    
Affiliation:
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenine / analogs & derivatives,  pharmacology
Adenosine Deaminase / antagonists & inhibitors*
Animals
Anti-HIV Agents / metabolism*
Biological Availability
Biological Transport / drug effects
Catheterization
Didanosine / analogs & derivatives*,  metabolism
Enzyme Inhibitors / pharmacology
Ileum / drug effects,  metabolism*
Intestinal Absorption* / drug effects
Male
Mesenteric Veins
Pentostatin / pharmacology
Permeability
Prodrugs / metabolism*,  pharmacokinetics
Purine Nucleosides / metabolism*,  pharmacokinetics
Purine-Nucleoside Phosphorylase / metabolism
Rats
Rats, Sprague-Dawley
Grant Support
ID/Acronym/Agency:
AI34133/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/6-chloro-9-(2,3-dideoxyribofuranosyl)-9H-purine; 0/Anti-HIV Agents; 0/Enzyme Inhibitors; 0/Prodrugs; 0/Purine Nucleosides; 134892-26-5/2'-fluoro-2',3'-dideoxyinosine; 53910-25-1/Pentostatin; 59262-86-1/9-(2-hydroxy-3-nonyl)adenine; 69655-05-6/Didanosine; 73-24-5/Adenine; EC 2.4.2.1/Purine-Nucleoside Phosphorylase; EC 3.5.4.4/Adenosine Deaminase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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