Glucuronide and glucoside conjugation of mycophenolic acid by human liver,kidney and intestinal microsomes

1 Mycophenolic acid (MPA) is primarily metabolized to a phenolic glucuronid e (MPAG) as well as to two further minor metabolites: an acyl glucuronide ( AcMPAG) and a phenolic glucoside (MPAG1s). This study presents investigatio ns of the formation of these metabolites by human liver (HLM), kidney (HKM) , and intestinal (HIM) microsomes, as well as by recombinant UDP-glucuronos yltransferases. 2 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 c oncentrations of MPA. Metabolite formation was followed by h.p.l.c. 3 All microsomes investigated formed both MPAG and AcMPAG. Whereas the effi ciency of MPAG formation was greater with HKM compared to HLM, AcMPAG forma tion was greater with HLM than HKM. HIM showed the lowest glucuronidation e fficiency and the greatest interindividual variation. The capacity for MPAG 1s formation was highest in HKM, while no glucoside was detected with HIM. 4 HKM produced a second metabolite when incubated with MPA and UDP-glucose, which was labile to alkaline treatment. Mass spectrometry of this metaboli te in the negative ion mode revealed a molecular ion of m/z 481 compatible with an acyl glucoside conjugate of MPA. 5 All recombinant UGTs investigated were able to glucuronidate MPA with K-M values ranging from 115.3 to 275.7 muM 1(-1) and V-max values between 29 a nd 106 pM min(-1) mg protein(-1). 6 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.