First-pass disposition of (2)-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 centra l nervous system exposure to CBV. The gut wall was determined to be the dom inant site of the first-pass activation of 6AC after lumenal administration . If subsequent delivery to the brain is desired, then such a first-pass ef fect might not be viewed favorably. Because the first-pass conversion of 6A C primarily takes place in the intestine by adenosine deaminase (ADA), quen ching of the intestinal activation of 6AC by oral administration of ADA inh ibitors may result in an increased 6AC bioavailability, and thus an improve d brain exposure to CBV. The objectives of the study were to determine whet her 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 concentr ations 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'-deoxyco formycin. 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 a ppeared to be relatively selective, allowing the choice of dose of inhibito r that would sufficiently inhibit the first-pass metabolism while leaving t he activation capacity in the systemic circulation unaltered. The systemic level of 6AC increased with the escalating dose of inhibitors, thus increas ing the driving force for passive uptake into the brain.