Acyclovir transport into human erythrocytes

• Published in: The Journal of biological chemistry 1988-07, Vol.263 (19), p.9285-9291
• Main Authors: Mahony, W B, Domin, B A, McConnell, R T, Zimmerman, T P
• Format: Article
• Language: English
• Subjects: Acyclovir - blood; Adenine - blood; Biological and medical sciences; Biological Transport - drug effects; Carbon Radioisotopes; Cell physiology; erythrocytes; Erythrocytes - metabolism; Fundamental and applied biological sciences. Psychology; Guanine - blood; Humans; Hypoxanthine; Hypoxanthines - blood; Idoxuridine - blood; Iodine Radioisotopes; Kinetics; man; Membrane and intracellular transports; Molecular and cellular biology; Nucleosides - pharmacology; Purines - pharmacology; Pyrimidines - pharmacology; Sucrose - blood; Tritium
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(19)76537-5

The mechanism of transport of the antiviral agent acyclovir (ACV) into human erythrocytes has been investigated. Initial velocities of ACV influx were determined with an “inhibitor-stop” assay that used papaverine to inhibit ACV influx rapidly and completely. ACV influx was nonconcentrative and appeared to be rate-saturable with a Km of 260 +/- 20 microM (n = 8). However, two lines of evidence indicate that ACV permeates the erythrocyte membrane by means other than the nucleoside transport system: 1) potent inhibitors (1.0 microM) of nucleoside transport (dipyridamole, 6-[(4-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine, and dilazep) had little (less than 8% inhibition) or no effect upon the influx of 5.0 microM ACV; and 2) a 100-fold molar excess of several purine and pyrimidine nucleosides had no inhibitory effect upon the influx of 1.0 microM ACV. However, ACV transport was inhibited competitively by adenine (Ki = 9.5 microM), guanine (Ki = 25 microM), and hypoxanthine (Ki = 180 microM). Conversely, ACV was a competitive inhibitor (Ki = 240-280 microM) of the transport of adenine (Km = 13 microM), guanine (Km = 37 microM), and hypoxanthine (Km = 180 microM). Desciclovir and ganciclovir, two compounds related structurally to ACV, were also found to be competitive inhibitors of acyclovir influx (Ki = 1.7 and 1.5 mM, respectively). These results indicate that ACV enters human erythrocytes chiefly via the same nucleobase carrier that transports adenine, guanine, and hypoxanthine.