Second International Congress Drug Therapy in HIV Infection 18-22 November 1994 Glasgow, UK

INTRACELLULAR PHOSPHORYLATION ANALOGUES IN VITRO AND IN VIVO OF NUCLEOSIDE

D.J. Back, M.G. Barry
Department of Pharmacology & Therapeutics, University of Liverpool, P.O. Box 147, Liverpool 1.69 3BX.

Int Cong Drug Therapy HIV 1994 Nov 18-22;2:Abstract No. 9.2
AIDS 1994, Vol. 8 (Suppl. 4);S7

The early licensing of antiretroviral agents for the treatment of patients with HIV infection has resulted in many of the fundamental questions relating to clinical pharmacology waiting to be answered. One important aspect relates to the formation of the active phosphorylated metabolites of nucleoside analogues. Our group and others have shown that plasma levels of zidovudine (ZDV) are unhelpful in predicting efficacy and toxicity. This is not surprising when we consider that all the nucleoside analogues (either licensed for use or in clinical development), ZDV, dideoxyinosine (ddI), dideoxycytidine (ddC), didehydro-dideoxythymidine (d4T) and deoxythiacytidine (3-TC) must undergo sequential phosphorylation to mono-, di- and triphosphate metabolites. It is the triphosphate metabolite which inhibits HIV reverse transcriptase thereby inhibiting viral replication. We have developed the methodology to measure nucleoside analogue phosphates in PBMCs in vitro and in vivo.

In a study on ZDV phosphorylation in seronegative volunteers and patients with HIV disease we have demonstrated that patients have significantly higher ZDV phosphate metabolites than volunteers. Elevated levels of the monophosphate metabolite account for this difference since the triphosphate levels are similar. Patients with a CD4 count < 100 x 10⁶/L have much higher ZDV phosphate levels, predominantly ZDV monophosphate. Utilizing information on phosphorylation may enable us to increase the benefit to risk ratio of nucleoside analogue therapy.

A further important area of study is drug interactions at the level of phosphorylation. in vitro phosphorylation studies may give useful leads to potential drug interactions involving nucleoside analogues in the patient population. We have screened numerous drugs for interaction with ZDV and ddC phosphate formation in stimulated PBMCs and Molt 4 cells. With ZDV, marked interactions have been seen with ribavirin and doxorubicin but no interaction with acyclovir, gancyclovir, foscarnet, ketoconazole, fluconazole, itraconazole, erythromycin, rifampicin, trimethoprim or sulphamethoxazole.

1994-11-18
9.2

Originally published in AIDS Volume 8, Supplement 4 and hosted with permission of the publisher Lippincott Williams & Wilkins, 250 Waterloo Road, London, SE1 8RD, UK. Tel: +44 (0)20 7981 0700 Fax: +44 (0) 7981 0701

Copyright © 1994 - Lippincott Williams & Wilkins. All rights reserved. All abstracts from the 2nd International Congress Drug Therapy in HIV Infection, appearing on the AEGiS web site, are protected by United States copyright law and may not be reproduced, distributed, transmitted, displayed, or otherwise published without the prior written permission of Lippincott Williams & Wilkins. You may not alter or remove any trademark, copyright or other notice. However, provided that you maintain all copyright and other notices contained therein, you may download material (one machine readable copy and one print copy per page) for your personal, non-commercial use only.

http://www.aidsonline.com http://www.ovid.com