Glucuronidation (GN) is a major metabolic inactivation pathway for AZT. Inhibition of GN may improve bioavailability and prolong elimination half-life of AZT. We synthesized a series of prodrugs of AZT containing UDP-GT substrates, such as probenecid, valproic acid, salicylic acid and o-aminobenzoic acid. It was expected that after enzymatic hydrolysis, the promoiety in hepatic cells may competitively block GN of AZT. However, the concentrations of the released promoiety were insignificant to cause alteration in GN rates. Addition of certain UDP-GT substrates directly to human hepatic microsomal fraction caused significant inhibition of GN. Microsomal fractions (2 mg/ml) and AZT (100 uM) were incubated in the absence or presence of various concentrations of the substrates (5 to 100 uM) at 37 C for 4 hr. AZT GN followed the Michaelis-Menton kinetics (apparent Km 2.2 mM). Valproic acid was the best competitive inhibitor of this series and at 50 uM completely blocked the GN of AZT. These results suggest that a combination of valproic acid and AZT may significantly increase bioavailability of AZT in AIDS patients.

Anthranilic Acids/METABOLISM/*PHARMACOLOGY Binding, Competitive Biological Availability Glucuronosyltransferase/*ANTAGONISTS & INHIB Half-Life Human Kinetics Liver/ENZYMOLOGY/*METABOLISM Microsomes, Liver/DRUG EFFECTS/ENZYMOLOGY/*METABOLISM Probenecid/METABOLISM/*PHARMACOLOGY Prodrugs/*METABOLISM/PHARMACOKINETICS Salicylic Acids/METABOLISM/*PHARMACOLOGY Valproic Acid/METABOLISM/*PHARMACOLOGY Zidovudine/*METABOLISM/PHARMACOKINETICS ABSTRACT

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