Glucuronidation of 3′-azido-3′-deoxythymidine catalyzed by human liver UDP-glucuronosyltransferase: Significance of nucleoside hydrophobicity and inhibition by xenobiotics

doi:10.1016/0006-2952(91)90319-Z

Biochemical Pharmacology

Volume 42, Issue 3, 15 July 1991, Pages 559-568

https://doi.org/10.1016/0006-2952(91)90319-Z Get rights and content

Abstract

The enzymatic glucuronidation of 3′-azido-3′-deoxythymidine (AZT) catalyzed by human liver microsomal UDP-glucuronosyltransferase (EC 2.4.1.17, UDPGT) was inhibited by a number of nucleoside analogs. The inhibitory potency of these nucleoside analogs correlated with their hydrophobicity (r² = 0.90, N = 13). Since similar results were obtained with solubilized UDPGT (r² = 0.87, N = 7), the affinity of the nucleosides for UDPGT was probably being assessed rather than the ability of the compounds to access the membrane-bound enzyme. Three homologous inhibitors, 3′-azido-2′,3′-dideoxyuridine (AzddU), 5-ethyl-AzddU, and 5-propyl-AzddU, were also studied as substrates of UDPGT. The substrate efficiency (V_max/K_m) of these three compounds and AZT also correlated with their hydrophobicity (r² = 0.94). Sixteen drugs that are structurally unrelated to nucleosides also inhibited the glucuronidation of AZT. The mechanism of inhibition was competitive for seven compounds tested. K_i, values were estimated from Dixon plots for nine other less soluble inhibitors; their mechanism of inhibition was assumed to be competitive. Since the peak physiological drug concentrations of the tested inhibitors are considerably less than their K_i values, none of these compounds are expected to strongly inhibit AZT glucuronidation in humans. However, the rank order of these drugs with respect to their inhibitory potential is probenecid > chrloramphenicol > naproxen > phenylbutazone > other drugs tested.

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Glucuronidation of 3′-azido-3′-deoxythymidine catalyzed by human liver UDP-glucuronosyltransferase: Significance of nucleoside hydrophobicity and inhibition by xenobiotics

Abstract

Lancet

Biochem Pharmacol

Lancet

Toxicol Appl Pharmacol

Biochem Pharmacol

Anal Biochem

Biochem Pharmacol

J Pharm Soc

J Pharm Sci

Biochem Pharmacol

Lancet

Pharmacol Ther

Trends Pharmacol Sci

Biochem Pharmacol

J Steroid Biochem

3′-Azido-3′-deoxythymidin (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro

Inhibition of replication and cytopathic effect of human T cell lymphotropic virus type III/lymphadenopathay-associated virus by 3′-azido-3′-deoxythymidhine in vitro

Antimicrob Agents Chemother

The efficacy of azdothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial

N Engl J Med

Survival experience among patients with AIDS receiving zidovudine: Follow-up of patients in a compassionate plea program

JAMA

Pharmacokinetics and metabolism of azidothymidine in the dog

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Tissue distribution and metabolic disposition of zidovudine in rats

Drug Metab Dispos

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Glucuronidation of Drugs and Other Compounds

3′-Azido-3′-deoxythmidine and acyclovir: Antiviral nucleoside analogues with unusual cell membrane permeation properties

The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial

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Clin Pharmacokinet

Alteration of zidovudine pharmacokinetics by probenecid in patients with AIDS or AIDS-related complex

Clin Pharmacol Ther

Probenecid inhibits the metabolic and renal clearances of zidovudine (AZT) in human volunteers

Pharm Res