title: Acyclovir transport into human erythrocytes.
abstract: 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.
authors: Experimental Therapy Department, Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
authors: W B
authors: WB
authors: Mahony
authors: B A
authors: BA
authors: Domin
authors: R T
authors: RT
authors: McConnell
authors: T P
authors: TP
authors: Zimmerman
mesh_terms: D000212:Acyclovir / Q000097:blood*; D000225:Adenine / Q000097:blood; D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes; D004912:Erythrocytes / Q000378:metabolism*; D006147:Guanine / Q000097:blood; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000097:blood; D007065:Idoxuridine / Q000097:blood; D007457:Iodine Radioisotopes; D007700:Kinetics; D009705:Nucleosides / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013395:Sucrose / Q000097:blood; D014316:Tritium
chemical_list: D002250:Carbon Radioisotopes; D007042:Hypoxanthines; D007457:Iodine Radioisotopes; D009705:Nucleosides; D011687:Purines; D011743:Pyrimidines; D014316:Tritium; D019271:Hypoxanthine; D013395:Sucrose; D006147:Guanine; D000225:Adenine; D007065:Idoxuridine; D000212:Acyclovir