PMID- 34698602
OWN - NLM
STAT- MEDLINE
DCOM- 20211203
LR  - 20211214
IS  - 1366-5928 (Electronic)
IS  - 0049-8254 (Linking)
VI  - 51
IP  - 11
DP  - 2021 Nov
TI  - UGT1A1 and UGT1A3 activity and inhibition in human liver and intestinal 
      microsomes and a recombinant UGT system under similar assay conditions using 
      selective substrates and inhibitors.
PG  - 1236-1246
LID - 10.1080/00498254.2021.1998732 [doi]
AB  - In vitro enzyme kinetics and inhibition data was compared for UGT1A1 and UGT1A3 
      isoforms under similar assay conditions using human liver microsomes (HLM), human 
      intestinal microsomes (HIM) and recombinant UGT (rUGT) enzyme systems.UGT1A1 
      catalysed beta-estradiol 3-beta-D-glucuronide formation showed allosteric sigmoidal 
      kinetics in all enzyme systems; while UGT1A3 catalysed CDCA 
      24-acyl-beta-D-glucuronide formation exhibited Michaelis-Menten kinetics in HLM, 
      substrate inhibition kinetics in HIM and rUGT systems. Corresponding K(m) or 
      S(50) concentrations of beta-estradiol and CDCA were employed in the respective UGT 
      inhibition studies.Atazanavir inhibited the production of beta-estradiol 
      3-beta-D-glucuronide with IC50 values of 0.54 microM and 0.16 microM in HLM and rUGT1A1, 
      respectively. But its inhibition potential was not observed in HIM, indicating 
      potential cross-talk with other high-affinity intestinal UGT isozymes. On the 
      other hand, zafirlukast, a pan UGT inhibitor, exhibited moderate inhibition in 
      HIM with an IC50 value of 16.70 microM. Lithocholic acid, inhibited the production of 
      CDCA 24-acyl-beta-D-glucuronide with IC50 values of 1.68, 1.84, and 12.42 microM in HLM, 
      rUGT1A3, and HIM, respectively.These results indicated that HLM, HIM, and rUGTs 
      may be used as complementary in vitro systems to evaluate hepatic and intestinal 
      UGT mediated DDIs at the screening stage.
FAU - Mullapudi, T V Radhakrishna
AU  - Mullapudi TVR
AD  - Department of Pharmacy, Birla Institute of Technology and Science-Pilani, 
      Hyderabad Campus, Hyderabad, India.
AD  - Drug Metabolism and Pharmacokinetics, PharmaJen Laboratories Private Limited, 
      A209 Technology Business Incubator, Birla Institute of Technology and 
      Science-Pilani, Hyderabad Campus, Hyderabad, India.
FAU - Ravi, Punna Rao
AU  - Ravi PR
AD  - Department of Pharmacy, Birla Institute of Technology and Science-Pilani, 
      Hyderabad Campus, Hyderabad, India.
FAU - Thipparapu, Ganapathi
AU  - Thipparapu G
AD  - Drug Metabolism and Pharmacokinetics, PharmaJen Laboratories Private Limited, 
      A209 Technology Business Incubator, Birla Institute of Technology and 
      Science-Pilani, Hyderabad Campus, Hyderabad, India.
LA  - eng
PT  - Journal Article
DEP - 20211110
PL  - England
TA  - Xenobiotica
JT  - Xenobiotica; the fate of foreign compounds in biological systems
JID - 1306665
RN  - 0 (Glucuronides)
RN  - 0 (Isoenzymes)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
SB  - IM
MH  - Glucuronides
MH  - *Glucuronosyltransferase/metabolism
MH  - Humans
MH  - Intestines
MH  - Isoenzymes/metabolism
MH  - Kinetics
MH  - Liver/metabolism
MH  - *Microsomes/metabolism
MH  - Microsomes, Liver/metabolism
OTO - NOTNLM
OT  - HIM
OT  - HLM
OT  - LC-MS/MS
OT  - UGT1A1
OT  - UGT1A3
OT  - drug-drug interactions
OT  - enzyme kinetics
EDAT- 2021/10/27 06:00
MHDA- 2021/12/15 06:00
CRDT- 2021/10/26 12:19
PHST- 2021/10/27 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/10/26 12:19 [entrez]
AID - 10.1080/00498254.2021.1998732 [doi]
PST - ppublish
SO  - Xenobiotica. 2021 Nov;51(11):1236-1246. doi: 10.1080/00498254.2021.1998732. Epub 
      2021 Nov 10.