The Main Role of UGT1A9 in the Hepatic Metabolism of Mycophenolic Acid and the Effects of Naturally Occurring Variants

Mycophenolic acid (MPA), a standard immunosuppressive drug, is characterized by unexplained highly variable pharmacokinetics in transplant recipients. The primary metabolic pathway of MPA is glucuronidation; however, literature reports are inconsistent and the contribution of all human UDP-glucuronosyltransferases (UGTs) has never been systematically assessed. Sixteen heterologously expressed UGTs were studied for MPA 7-O-glucuronidation and compared with liver, kidney, and intestine microsomes. For direct measurement of MPA and mycophenolic acid 7-O-glucuronide (MPAG), we used a liquid chromatography-mass spectrometry protocol. Metabolic studies demonstrated that the glucuronidation of MPA in humans occurs mainly in the liver at variable rates, as well as in the kidney and the intestine. Kinetic data normalized for UGT expression levels point to 1A8 and 1A9 as the main UGTs, as well as to low-activity enzymes, 1A1, 1A7, and 1A10. According to their expression profiles, 1A8 and 1A9 are proposed, respectively, as the main extra-hepatic and the only hepatic enzymes involved. The effects of naturally occurring 1A8 ((*)2 and (*)3) and 1A9 ((*)2 and (*)3) variants on MPA 7-O-glucuronidation were studied and data suggest that the C(277)Y of 1A8 and the M(33)T of 1A9 may influence MPAG levels. A number of low-activity alleles were also identified in 1A1 [(*)6 (G(71)R), (*)7 (Y(486)D), (*)27 (P(229)Q), and (*)35 (L(233)R)], 1A7 [(*)3 (K(129)K(131)R(208)), (*)4 (R(208)), (*)5 (S(115)), (*)8 (K(129)K(131)D(139)R(208)), and (*)9 (S(115)K(129)K(131))], and 1A10 [(*)2 (E(139)K)]. Our study provides preliminary evidences that genetic factors, especially in the hepatic UGT1A9, may contribute to the variability of MPA pharmacokinetics observed in transplant patients.