First-pass disposition of (-)-6-aminocarbovir in rats: II. Inhibition of intestinal first-pass metabolism.
A CBV [(-)-carbovir, (-)-carbocyclic 2',3'-didehydro-2', 3'-dideoxyguanosine] prodrug, 6AC [(-)-6-aminocarbovir, (-)-carbocyclic 2',3'-didehydro-2', 3'-dideoxy-6-deoxy-6-aminoguanosine], was previously evaluated in rats, and it exhibited superiority to the parent drug in increasing systemic and central nervous system exposure to CBV. The gut wall was determined to be the dominant site of the first-pass activation of 6AC after lumenal administration. If subsequent delivery to the brain is desired, then such a first-pass effect might not be viewed favorably. Because the first-pass conversion of 6AC primarily takes place in the intestine by adenosine deaminase (ADA), quenching of the intestinal activation of 6AC by oral administration of ADA inhibitors may result in an increased 6AC bioavailability, and thus an improved brain exposure to CBV. The objectives of the study were to determine whether the ADA inhibitors 2'-deoxycoformycin and erythro-9-(2-hydroxy-3-nonyl)adenine were capable of achieving a substantial and selective inhibition of gut wall activation of 6AC, and to determine whether the systemic concentrations of 6AC would be thus increased. Thirty-nine male Sprague-Dawley rats were divided into two groups. One group received 6AC by either the portal vein or intralumenally with the coadministration of intralumenal 2'-deoxycoformycin. Similarly, the other group received 6AC with coadministration of erythro-9-(2-hydroxy-3-nonyl)adenine. Substantial suppression of the first-pass conversion of 6AC was achieved with both inhibitors. This inhibition appeared to be relatively selective, allowing the choice of dose of inhibitor that would sufficiently inhibit the first-pass metabolism while leaving the activation capacity in the systemic circulation unaltered. The systemic level of 6AC increased with the escalating dose of inhibitors, thus increasing the driving force for passive uptake into the brain.
Zimmerman
C L
CL
Departments of Pharmaceutics and Medicinal Chemistry, University of Minnesota, College of Pharmacy, Minneapolis, Minnesota, USA. zimme005@tc.umn.edu
Wen
Y
Y
Remmel
R P
RP
D000243:Adenosine Deaminase / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D015224:Dideoxynucleosides / Q000378:metabolism / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D058892:Adenosine Deaminase Inhibitors; D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D004791:Enzyme Inhibitors; D011355:Prodrugs; C069735:6-aminocarbovir; D000243:Adenosine Deaminase