Zidovudine glucuronidation in human liver: interindividual variability

Area of Science:

• Pharmacology
• Biochemistry
• Hepatology

Background:

• Zidovudine (3'-azido-3'-deoxythymidine) is a key drug for treating AIDS, inhibiting HIV replication.
• The drug undergoes extensive metabolism via glucuronidation, leading to presystemic elimination.
• Understanding the variability of zidovudine glucuronosyl transferase is crucial for optimizing therapy.

Purpose of the Study:

• To investigate and characterize the variability and frequency distribution of zidovudine glucuronosyl transferase activity in human liver specimens.
• To establish a reliable assay for measuring zidovudine glucuronidation.
• To explore potential interactions with endogenous bilirubin and determine kinetic parameters.

Main Methods:

• Development of a rapid radiometric assay for 14C-zidovudine glucuronidation.
• Measurement of unreacted zidovudine via organic solvent extraction.
• Quantification of radioactivity in the aqueous phase residue to determine zidovudine glucuronide formation.
• Analysis of enzyme kinetics using Michaelis-Menten models.

Main Results:

• Zidovudine glucuronidation rates exhibited significant variability (over 1 order of magnitude) and a positively skewed distribution in 93 human liver samples.
• Enzyme activity was independent of patient sex and age.
• Endogenous bilirubin concentrations (2.2–13.2 microM) did not affect the rate of zidovudine glucuronidation.
• Michaelis-Menten kinetics were observed, with an average K(m) of 2.89 mM, showing a 2-fold range.

Conclusions:

• The rate of zidovudine glucuronidation in the human liver displays considerable inter-individual variability.
• This variability, characterized by a skewed distribution, may significantly influence patient exposure to zidovudine.
• Understanding these pharmacokinetic variations is essential for tailoring zidovudine therapy and improving treatment outcomes in AIDS patients.