Domin B A, Mahony W B, Zimmerman T P
Experimental Therapy Division, Wellcome Research Laboratories, Research Triangle Park, NC 27709.
Biochem Pharmacol. 1991 Jun 21;42(1):147-52. doi: 10.1016/0006-2952(91)90693-y.
The mechanism of transport of desciclovir (DCV)--a structural analogue and prodrug of acyclovir (ACV) which provides an improved oral bioavailability of ACV--was investigated in human erythrocytes with a "papaverine-stop" assay. DCV influx was nonconcentrative, linearly dependent on DCV concentration (0.9 microM to 15 mM), insensitive (less than or equal to 20% inhibition) to nucleobases, nucleosides, or potent inhibitors of nucleoside transport, and occurred without permeant metabolism. However, DCV was a weak competitive inhibitor of the influx of adenine (Ki = 1.3 mM) and of 5-iodo-2'-deoxyuridine (Ki = 2.9 mM). permeants of the erythrocyte nucleobase and nucleoside carriers, respectively. This indicates that DCV has an affinity for both of these transporters, even though it appears not to be an effective permeant. We conclude that, in contrast to ACV which enters human erythrocytes primarily via the nucleobase carrier, DCV permeates these cells chiefly (greater than or equal to 80%) by nonfacilitated diffusion. This mechanistic difference in transport between ACV and DCV is attributed to differences in their desolvation energies and suggests an explanation for the differences in the oral bioavailability of ACV which is observed after the administration of these two "acyclic nucleosides."
地昔洛韦（DCV）是阿昔洛韦（ACV）的结构类似物和前体药物，能提高ACV的口服生物利用度。本研究采用“罂粟碱阻断”试验，在人红细胞中研究了DCV的转运机制。DCV内流是非浓缩性的，与DCV浓度（0.9微摩尔/升至15毫摩尔/升）呈线性相关，对碱基、核苷或核苷转运的强效抑制剂不敏感（抑制率小于或等于20%），且不发生渗透代谢。然而，DCV是腺嘌呤（Ki = 1.3毫摩尔/升）和5-碘-2'-脱氧尿苷（Ki = 2.9毫摩尔/升）内流的弱竞争性抑制剂，分别是红细胞碱基和核苷载体的渗透剂。这表明DCV对这两种转运体都有亲和力，尽管它似乎不是一种有效的渗透剂。我们得出结论，与主要通过碱基载体进入人红细胞的ACV不同，DCV主要（大于或等于80%）通过非易化扩散渗透这些细胞。ACV和DCV在转运机制上的这种差异归因于它们去溶剂化能的不同，并为这两种“无环核苷”给药后观察到的ACV口服生物利用度差异提供了解释。
