PMID- 11226133
OWN - NLM
STAT- MEDLINE
DCOM- 20010621
LR  - 20181113
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 132
IP  - 5
DP  - 2001 Mar
TI  - Glucuronide and glucoside conjugation of mycophenolic acid by human liver, kidney 
      and intestinal microsomes.
PG  - 1027-34
AB  - Mycophenolic acid (MPA) is primarily metabolized to a phenolic glucuronide (MPAG) 
      as well as to two further minor metabolites: an acyl glucuronide (AcMPAG) and a 
      phenolic glucoside (MPAG1s). This study presents investigations of the formation 
      of these metabolites by human liver (HLM), kidney (HKM), and intestinal (HIM) 
      microsomes, as well as by recombinant UDP-glucuronosyltransferases. HLM (n=5), 
      HKM (n=6), HIM (n=5) and recombinant UGTs were incubated in the presence of 
      either UDP-glucuronic acid or UDP-glucose and various concentrations of MPA. 
      Metabolite formation was followed by h.p.l.c. All microsomes investigated formed 
      both MPAG and AcMPAG. Whereas the efficiency of MPAG formation was greater with 
      HKM compared to HLM, AcMPAG formation was greater with HLM than HKM. HIM showed 
      the lowest glucuronidation efficiency and the greatest interindividual variation. 
      The capacity for MPAGls formation was highest in HKM, while no glucoside was 
      detected with HIM. HKM produced a second metabolite when incubated with MPA and 
      UDP-glucose, which was labile to alkaline treatment. Mass spectrometry of this 
      metabolite in the negative ion mode revealed a molecular ion of m/z 481 
      compatible with an acyl glucoside conjugate of MPA. All recombinant UGTs 
      investigated were able to glucuronidate MPA with K:(M:) values ranging from 115.3 
      to 275.7 microM l(-1) and V(max) values between 29 and 106 pM min(-1) mg 
      protein(-1). Even though the liver is the most important site of MPA 
      glucuronidation, extrahepatic tissues particularly the kidney may play a 
      significant role in the overall biotransformation of MPA in man. Only kidney 
      microsomes formed a putative acyl glucoside of MPA.
FAU - Shipkova, M
AU  - Shipkova M
AD  - Abteilung fur Klinische Chemie, Georg-August-Universitat, Robert-Koch-Strasse 40, 
      D-37075 Gottingen, Germany. maria.shipkova@med.uni-goettingen.de
FAU - Strassburg, C P
AU  - Strassburg CP
FAU - Braun, F
AU  - Braun F
FAU - Streit, F
AU  - Streit F
FAU - Grone, H J
AU  - Grone HJ
FAU - Armstrong, V W
AU  - Armstrong VW
FAU - Tukey, R H
AU  - Tukey RH
FAU - Oellerich, M
AU  - Oellerich M
FAU - Wieland, E
AU  - Wieland E
LA  - eng
GR  - R01 GM049135/GM/NIGMS NIH HHS/United States
GR  - GM49135/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Glucuronates)
RN  - 0 (Glucuronides)
RN  - 54TS5J9T0K (mycophenolic acid glucuronide)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
RN  - HU9DX48N0T (Mycophenolic Acid)
SB  - IM
MH  - Glucuronates/*metabolism
MH  - Glucuronides
MH  - Glucuronosyltransferase/*metabolism
MH  - Humans
MH  - Intestines/*enzymology
MH  - Kidney/*enzymology
MH  - Microsomes/*enzymology
MH  - Microsomes, Liver/enzymology
MH  - Mycophenolic Acid/analogs & derivatives/*metabolism
PMC - PMC1572641
EDAT- 2001/02/28 10:00
MHDA- 2001/06/22 10:01
PMCR- 2002/03/01
CRDT- 2001/02/28 10:00
PHST- 2001/02/28 10:00 [pubmed]
PHST- 2001/06/22 10:01 [medline]
PHST- 2001/02/28 10:00 [entrez]
PHST- 2002/03/01 00:00 [pmc-release]
AID - 0703898 [pii]
AID - 10.1038/sj.bjp.0703898 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2001 Mar;132(5):1027-34. doi: 10.1038/sj.bjp.0703898.