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Antimicrobial Agents and Chemotherapy, July 1998, p. 1654-1658, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Zidovudine Azido-Reductase in Human Liver Microsomes: Activation by Ethacrynic Acid, Dipyridamole, and Indomethacin and Inhibition by Human Immunodeficiency Virus Protease Inhibitors

Shirin Fayz and T. Inaba*

Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Received 24 October 1997/Returned for modification 21 February 1998/Accepted 9 May 1998

AZT (zidovudine, 3'-azido-3'-deoxythymidine), although metabolized primarily to AZT-glucuronide, is also metabolized to 3'-amino-3'-deoxythmidine (AMT) by reduction of the azide to an amine. The formation of the myelotoxic metabolite AMT has not been well characterized, but inhibition of AMT formation would be of therapeutic benefit. The aim of this study was to identify compounds that inhibit AMT formation. Using human liver microsomes under anaerobic conditions and [2-14C]AZT, Km values of AZT azido-reductase, estimated by radio-thin-layer chromatography, were 2.2 to 3.5 mM (n = 3). Oxygen completely inhibited this NADPH-dependent reduction. Thirteen of the 28 compounds tested inhibited the formation of AMT. In addition to the CYP3A4 inhibitors ketoconazole, fluconazole, indinavir, ritonavir, and saquinavir, metyrapone strongly inhibited AMT formation. An unexpected finding was the more-than-twofold increase in AMT formation in the presence of ethacrynic acid, dipyridamole, or indomethacin. Such activation of toxic metabolite formation would impair drug therapy.

* Corresponding author. Mailing address: Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada. Phone: 416-978-2728. Fax: 416-978-7095. E-mail: t.inaba{at}utoronto.ca.

Antimicrobial Agents and Chemotherapy, July 1998, p. 1654-1658, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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