PMID- 20304965
OWN - NLM
STAT- MEDLINE
DCOM- 20100820
LR  - 20151119
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 38
IP  - 6
DP  - 2010 Jun
TI  - Investigation into UDP-glucuronosyltransferase (UGT) enzyme kinetics of 
      imidazole- and triazole-containing antifungal drugs in human liver microsomes and 
      recombinant UGT enzymes.
PG  - 923-9
LID - 10.1124/dmd.109.030676 [doi]
AB  - Imidazoles and triazoles represent major classes of antifungal azole derivatives. 
      With respect to UDP-glucuronosyltransferase (UGT) enzymes, the drug metabolism 
      focus has mainly concentrated on their inhibitory effects with little known about 
      azoles as substrates for UGTs. N-Glucuronide metabolites of the imidazole 
      antifungals, tioconazole and croconazole, have been reported, but there are 
      currently no reports of N-glucuronidation of triazole antifungal agents. In this 
      study, evidence for glucuronidation of azole-containing compounds was studied in 
      human liver microsomes (HLM). When a glucuronide metabolite was identified, 
      azoles were incubated in 12 recombinant UGT (rUGT) enzymes, and enzyme kinetics 
      were determined for the UGT with the most intense glucuronide peak. Six imidazole 
      antifungals, three triazoles, and the benzodiazepine alprazolam (triazole) were 
      evaluated in this study. All compounds investigated were identified as substrates 
      of UGT. UGT1A4 was the main enzyme involved in the metabolism of all compounds 
      except for fluconazole, which was mainly metabolized by UGT2B7, probably 
      mediating its O-glucuronide metabolism. UGT1A3 was also found to be involved in 
      the metabolism of all imidazoles but not triazoles. In both HLM and rUGT K(m) 
      values were lower for imidazoles (14.8-144 microM) than for triazoles (158-3037 
      microM), with the exception of itraconazole (8.4 microM). All of the imidazoles 
      studied inhibited their own metabolism at high substrate concentrations. In terms 
      of UGT1A4 metabolism, itraconazole showed kinetic features characteristic of 
      imidazole rather than triazole antifungals. This behavior is attributed to the 
      physicochemical properties of itraconazole that are similar to those of 
      imidazoles in terms of clogP.
FAU - Bourcier, Karine
AU  - Bourcier K
AD  - Pfizer Global R&D, Ramsgate Rd., Sandwich, Kent CT13 9NJ, UK. 
      karine.bourcier@pfizer.com
FAU - Hyland, Ruth
AU  - Hyland R
FAU - Kempshall, Sarah
AU  - Kempshall S
FAU - Jones, Russell
AU  - Jones R
FAU - Maximilien, Jacqueline
AU  - Maximilien J
FAU - Irvine, Nicola
AU  - Irvine N
FAU - Jones, Barry
AU  - Jones B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100319
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Antifungal Agents)
RN  - 0 (Glucuronides)
RN  - 0 (Imidazoles)
RN  - 0 (Triazoles)
RN  - 446254H55G (croconazole)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
RN  - S57Y5X1117 (tioconazole)
SB  - IM
MH  - Antifungal Agents/metabolism/*pharmacokinetics
MH  - Dose-Response Relationship, Drug
MH  - Glucuronides/metabolism
MH  - Glucuronosyltransferase/chemistry/drug effects/*metabolism
MH  - Humans
MH  - Imidazoles/chemistry/immunology/*pharmacokinetics
MH  - Microsomes, Liver/*chemistry
MH  - Stereoisomerism
MH  - Substrate Specificity
MH  - Triazoles/chemistry
EDAT- 2010/03/23 06:00
MHDA- 2010/08/21 06:00
CRDT- 2010/03/23 06:00
PHST- 2010/03/23 06:00 [entrez]
PHST- 2010/03/23 06:00 [pubmed]
PHST- 2010/08/21 06:00 [medline]
AID - dmd.109.030676 [pii]
AID - 10.1124/dmd.109.030676 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2010 Jun;38(6):923-9. doi: 10.1124/dmd.109.030676. Epub 2010 
      Mar 19.