Phenobarbital inducible UDP-glucuronosyltransferase is responsible for glucuronidation of 3′-azido-3′-deoxythymidine: Characterization of the enzyme in human and rat liver microsomes

Haumont, Marc; Magdalou, Jacques; Lafaurie, C.; Ziegler, Jean-Claude; Siest, Gérard; Colin, J. N.

doi:10.1016/0003-9861(90)90442-2

Cited by 35 publications

(11 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Three of the four groups published very similar kinetic parameters for the glucuronidation of zidovudine by human liver microsomes (K m = 2.2-3.3mM, V max = 58~162 nmoles h-1 rnq"). A comparable V max (59 nmoles h-1 mg-1 ) but higher K m (13.4mM) were reported by Haumont et al (1990). These investigators reported nearly identical kinetic parameters using monkey liver and found the relative rate of glucuronidation in human microsomes to be slightly higher than that in monkey microsomes; both sources gave signficantly higher rates than microsomes from Wistar or Gunn rats.…”

Section: In Vitro Studiessupporting

confidence: 57%

“…Liebes et al (1988) reported that the human hepatoma cell line, Hep-G2, can convert zidovudine to GAZT. The glucuronidation of zidovudine was demonstrated recently in microsomes prepared from human liver as well as rat, pig and rhesus monkey liver (Resetar and Spector, 1989;Cretton et al, 1990;Haumont et al, 1990;Sim and Back, 1990). Three of the four groups published very similar kinetic parameters for the glucuronidation of zidovudine by human liver microsomes (K m = 2.2-3.3mM, V max = 58~162 nmoles h-1 rnq").…”

Section: In Vitro Studiesmentioning

confidence: 73%

See 1 more Smart Citation

Species Differences in the Metabolism and Disposition of Antiviral Nucleoside Analogues: 2. Zidovudine

Good

Miranda

1992

Antivir Chem Chemother

View full text Add to dashboard Cite

SummaryPreclinical and clinical studies on the disposition of zidovudine, a thymidine analogue with potent activity against human immunodeficiency virus, identified significant species differe.nces in the metabolism and elimination of the drug. Zidovudine was extensively metabolized to the 5' -O~glucuronide in man and other primates. Rabbits and dogs were intermediate in their extent of biotransformation to the glucuronide conjugate, whereas rats and mice excreted the drug largely unchanged. Decreased metabolism was compensated by increased renal elimination, such that plasma elimination phase half-lives for zidovudine were similar (0.6-1.1 h) in all species. Rapid and extensive absorption and considerable penetration into tissues were also observed for all species studied. Only in the brain and testes were drug levels less than in plasma, although effective antiviral concentrations of zidovudine were achieved in brain and CSF. This review summarizes the variety of studies of the absorption, distribution, metabolism, and elimination of zidovudine in several species, including humans.

show abstract

Section: In Vitro Studiessupporting

confidence: 57%

Section: In Vitro Studiesmentioning

confidence: 73%

Species Differences in the Metabolism and Disposition of Antiviral Nucleoside Analogues: 2. Zidovudine

Good

Miranda

1992

Antivir Chem Chemother

View full text Add to dashboard Cite

show abstract

“…Furthermore, although rifampin usually induces liver enzymes involved in phase 1 metabolism, such as oxidation and dealkylation (1,17), it has been demonstrated that it can also increase the glucuronidation of certain drugs, e.g., paracetamol (21). To our knowledge, induction of the glucuronidation of zidovudine by rifampin has not been demonstrated before, but induction by phenobarbital has been reported (10). Therefore, the interaction between rifampin (or rifabutin) and zidovudine is likely to be caused by induction of glucuronidation enzymes in the liver.…”

Section: Discussionmentioning

confidence: 87%

Pharmacokinetic interaction between rifampin and zidovudine

Burger

Meenhorst

Koks

et al. 1993

Antimicrob Agents Chemother

View full text Add to dashboard Cite

A potential pharmacokinetic interaction between rifampin (Rimactan, Rifadin) and zidovudine (AZT, Retrovir) was investigated in the population of human immunodeficiency virus-infected patients at our hospital. The results from four patients who were on long-term (26 months) combination therapy with zidovudine and rifampin are presented. In all cases of combined use of zidovudine and rifampin, a lower area under the plasma concentration-time curve (AUC) and, consequently, a higher apparent clearance of zidovudine were found, compared with a reference population of zidovudine users. Patients had a low to normal maximum concentration of zidovudine in plasma. Elimination half-lives were normal in all but one patient. Zidovudine glucuronide concentrations were determined in three patients and three control subjects. The patients all had relatively higher peak plasma concentrations and higher AUCs of zidovudine glucuronide than the control subjects. In one patient, zidovudine and zidovudine glucuronide were also measured 2.5 months after discontinuation of rifampin. The AUC of zidovudine increased by a factor of 2. These data are in agreement with an enzyme-inducing effect of rifampin on the glucuronidation of zidovudine. They indicate that long-term combination therapy of rifampin and zidovudine leads to increased clearance of zidovudine, which may have therapeutic consequences.

show abstract

“…Clofibrate (0.3%, w/w; Sigma) was added to the rodent chow and given to rats for 7 days. As previously reported by Haumont et al (1990), the doses of 3-MC, phenobarbital, and clofibrate were chosen for selectively inducing the UGT isoforms that glucuronidate planar phenols, bulky phenols, and bilirubin, respectively. In these conditions, glucuronidation of 3Ј-azido-3Ј-deoxythymidine was enhanced 4 times by phenobarbital, glucuronidation of 1-naphthol was enhanced 6-fold by 3-MC, and glucuronidation of bilirubin was enhanced 2-fold by clofibrate.…”

Section: Methodsmentioning

confidence: 99%

Characterization of Catechol Glucuronidation in Rat Liver

Antonio¹,

Grillasca²,

Taskinen³

et al. 2002

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

This paper is available online at http://dmd.aspetjournals.org ABSTRACT:Catechols are a class of substances from natural or synthetic origin that contain a 1,2-dihydroxybenzene group. We have characterized the glucuronidation by rat liver microsomes and by the rat liver recombinant UDP-glucuronosyltransferase isoforms UGT1A6 and UGT2B1 of a series of 42 structurally diverse catechols, including neurotransmitters, polyphenols, drugs, and catechol estrogens. Small catechols (4-nitrocatechol, 2,3-dihydroxybenzaldehyde, 4-methylcatechol, and tetrachlorocatechol), tyrphostine A23, and octylgallate were glucuronidated at the highest rate by rat liver microsomes and the recombinant enzymes. By contrast, polyphenols from green tea (catechin and related compounds), 3,5-dinitrocatechol, the catechol-O-methyltransferase inhibitor drugs (entacapone, nitecapone, and tolcapone), the carboxyl catechols (gallic acid and dihydroxybenzoic acid derivatives), and the neurotransmitters and dopaminergic drugs, except dobutamine, were glucuronidated at low rate. Glucuronidation of most catechols was increased upon treatment of rats by 3-methylcholanthrene (3-MC) or Aroclor 1254. No induction was observed after administration of phenobarbital and clofibrate or treatment with catechols. Partial least-squares modeling was carried out to explain the variations of glucuronidation activity by liver microsomes of nontreated and 3-MC-treated rats. The model developed explained 82% and predicted 61% of the variations of glucuronidation activities. Among the 17 electronic and substructure parameters used that characterize the catechols, the hydrophobicity/ molar volume ratio of catechols showed a strong positive correlation with the glucuronidation rate. The effect of the pK a of the catechol group was modeled to be nonlinear, the optimal pK a value for glucuronidation being between 8 and 9. Hydrogen bonding and steric effects also were important to account for to predict the glucuronidation rates.

show abstract

Phenobarbital inducible UDP-glucuronosyltransferase is responsible for glucuronidation of 3′-azido-3′-deoxythymidine: Characterization of the enzyme in human and rat liver microsomes

Cited by 35 publications

References 18 publications

Species Differences in the Metabolism and Disposition of Antiviral Nucleoside Analogues: 2. Zidovudine

Species Differences in the Metabolism and Disposition of Antiviral Nucleoside Analogues: 2. Zidovudine

Pharmacokinetic interaction between rifampin and zidovudine

Characterization of Catechol Glucuronidation in Rat Liver

Contact Info

Product

Resources

About