The glucuronidation of mycophenolic acid by human liver, kidney and jejunum microsomes.
OBJECTIVE
To estimate the relative contribution of liver, kidney and jejunum to MPA elimination via glucuronidation from in vitro kinetic data.


METHODS
The kinetics of MPA glucuronidation by human liver, kidney and jejunum microsomes were characterized. Mycophenolic acid glucuronide (MPAG) concentrations in microsomal incubations were determined using a specific h.p.l.c. procedure. Non-specific microsomal binding of MPA was excluded using an equilibrium dialysis approach.


RESULTS
Microsomes from all three tissues catalysed the conversion of MPA to MPAG. Mean microsomal intrinsic clearances for MPAG formation by liver, kidney and jejunum microsomes were 46.6, 73.5 and 24.5 microl (min mg)(-1), respectively. When extrapolated to the whole organ, however, hepatic intrinsic clearance was 21- and 38-fold higher than the respective intrinsic clearances for kidney and small intestine.


CONCLUSIONS
The data suggest that the liver is the organ primarily responsible for the systemic clearance of MPA, with little contribution from the kidney, and that the small intestine would be expected to contribute to first-pass extraction to a minor extent only.
Bowalgaha
K
K
Department of Clinical Pharmacology, Flinders Medical Centre and Flinders University of South Australia, Bedford Park, Adelaide, SA, Australia.
Miners
J O
JO
D005965:Glucuronates / Q000378:metabolism*; D006801:Humans; D007583:Jejunum / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D009173:Mycophenolic Acid / Q000378:metabolism*
D005965:Glucuronates; D009173:Mycophenolic Acid