Isolation and characterization of an ether glucuronide of zidovudine, a major metabolite in monkeys and humans.
A major metabolite of zidovudine (3'-azido-3'-deoxythymidine, AZT), which previously had not been observed in a variety of experimental animals, was identified in samples of plasma and urine from cynomolgus monkeys and a patient treated with AZT. The urinary recoveries of metabolite from the monkeys and the patient were, respectively, 1.5- and 6.9-fold higher than the recoveries of unchanged drug. The metabolite was purified in gram quantities from the urines of the monkeys and the patient and was identified enzymatically, using beta-glucuronidase and a specific inhibitor of the enzyme, as a glucuronide conjugate of AZT. The metabolite was formed in vitro by incubating AZT with preparations of human liver in the presence of UDP-glucuronic acid. In addition, the metabolite was prepared synthetically and physical characterizations--including microanalysis and UV, IR, NMR and mass spectra--of compound from all three sources were identical and confirmed the metabolite to be the 5'-O-beta-D-glucuronide of AZT.
Good
S S
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Division of Experimental Therapy, Burroughs Wellcome Co., Research Triangle Park, NC 27709.
Koble
C S
CS
Crouch
R
R
Johnson
R L
RL
Rideout
J L
JL
de Miranda
P
P
D000818:Animals; D001711:Biotransformation; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology; D013045:Species Specificity; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood / Q000378:metabolism* / Q000652:urine
D015215:Zidovudine; C055886:3'-azido-3'-deoxy-5'-O-beta-glucopyranuronosylthymidine; D005966:Glucuronidase