Zimmerman C L, Wen Y, Remmel R P
Departments of Pharmaceutics and Medicinal Chemistry, University of Minnesota, College of Pharmacy, Minneapolis, Minnesota, USA.
Drug Metab Dispos. 2000 Jun;28(6):672-9.
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.
一种CBV[(-)-卡波韦，(-)-碳环2',3'-二脱氢-2',3'-二脱氧鸟苷]前药，6AC[(-)-6-氨基卡波韦，(-)-碳环2',3'-二脱氢-2',3'-二脱氧-6-脱氧-6-氨基鸟苷]，先前已在大鼠中进行评估，在增加全身和中枢神经系统对CBV的暴露方面，它表现出优于母体药物的特性。经测定，肠壁是腔内给药后6AC首过激活的主要部位。如果希望随后将药物输送到大脑，那么这种首过效应可能并不理想。由于6AC的首过转化主要在肠道中由腺苷脱氨酶（ADA）进行，通过口服ADA抑制剂抑制6AC的肠道激活可能会提高6AC的生物利用度，从而改善大脑对CBV的暴露。该研究的目的是确定ADA抑制剂2'-脱氧助间型霉素和赤型-9-(2-羟基-3-壬基)腺嘌呤是否能够对6AC的肠壁激活实现显著且选择性的抑制，以及确定6AC的全身浓度是否会因此增加。39只雄性Sprague-Dawley大鼠被分为两组。一组通过门静脉或腔内给予6AC，并同时腔内给予2'-脱氧助间型霉素。同样，另一组给予6AC并同时给予赤型-9-(2-羟基-3-壬基)腺嘌呤。两种抑制剂均实现了对6AC首过转化的显著抑制。这种抑制似乎具有相对选择性，允许选择能够充分抑制首过代谢同时不改变全身循环中激活能力的抑制剂剂量。随着抑制剂剂量的增加，6AC的全身水平升高，从而增加了被动摄取进入大脑的驱动力。
