A novel zidovudine-uridine dimer as an anti-HIV agent with increased therapeutic index (Meeting abstract). NLM AIDSLINE Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

Click here to return to AIDSLINE main menu
DonateNow
Print this Article


A novel zidovudine-uridine dimer as an anti-HIV agent with increased therapeutic index (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 35:A2011 1994. Unique Identifier : AIDSLINE ICDB/95603697
Lu Q; Gogu SR; Bandara N; Rider B; Garry RF; Agrawal KC; Dept. of Pharmacology, Tulane Univ. Sch. of Medicine, New; Orleans, LA 70112

Abstract: Zidovudine (AZT)-induced hematopoietic toxicity remains a major limiting factor in the clinical management of AIDS. Since uridine has been shown to protect the bone marrow cells (BMC) from AZT toxicity, we have synthesized a novel phosphate diester of AZT and uridine. AZT-5'-beta-cyanoethylphosphate was condensed with 2',3'-O-isopropylideneuridine which upon hydrolysis produced the desired compound. The ED90 of AZT-phosphate-uridine (AZT-P-U) dimer was 0.01 uM vs 0.1 uM for AZT against HIV-1 in MT4 cells. The AZT-P-U was 5-fold less toxic in the CFU-E assay using murine BMC with IC50 of 3.74 uM vs 0.78 uM for AZT. The preliminary pharmacokinetic experiments in mice (23.4 mg/kg ip equivalent to 10 mg/kg of AZT) indicated that AZT-P-U remained intact for up to 2 hr in serum and released AZT with a peak plasma concentration of 6.5 ug/ml. Lack of 5'-OH group in AZT-P-U suggests that it may not undergo first pass metabolism to 5'-O-glucuronide. These data indicate that AZT-P-U possesses potential advantages over AZT due to higher therapeutic index and better pharmacokinetic properties.
Keywords: Animal Biotransformation Colony-Forming Units Assay Comparative Study Hematopoietic Stem Cells/CYTOLOGY/DRUG EFFECTS/PATHOLOGY HIV-1/*DRUG EFFECTS/PHYSIOLOGY Mice Structure-Activity Relationship Uridine/PHARMACOKINETICS/TOXICITY Zidovudine/*ANALOGS & DERIVATIVES/CHEMICAL SYNTHESIS/METABOLISM/ PHARMACOKINETICS/TOXICITY ABSTRACTKWDanimalbiotransformationcolony-formingunitsassaycomparativestudyhematopoieticstemcells/cytology/drugeffects/pathologyhiv-1/KWDdrugeffects/physiologymicestructure-activityrelationshipuridine/pharmacokinetics/toxicityzidovudine/KWDanalogs&derivatives/chemicalsynthesis/metabolism/pharmacokinetics/toxicityabstract
950228
M9521047

Copyright © 1995 - National Library of Medicine. Reproduced under license with the National Library of Medicine, Bethesda, MD.

AEGiS is a 501(c)3, not-for-profit, tax-exempt, educational corporation. AEGiS is made possible through unrestricted funding from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Bristol-Myers Squibb Company, Elton John AIDS Foundation, Gill Foundation, the National Library of Medicine, Quest Diagnostics, Roche and Trimeris, and donations from users like you. Always watch for outdated information. This article first appeared in 1995. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 1995. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .