Proc Annu Meet Am Assoc Cancer Res; 33:A2389 1992. Unique Identifier :
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,
Acids/METABOLISM/*PHARMACOLOGY Valproic Acid/METABOLISM/*PHARMACOLOGY