Rifampin induces alterations in mycophenolic acid glucuronidation and elimination: implications for drug exposure in renal allograft recipients.
BACKGROUND
Exposure to mycophenolic acid (MPA) and its main metabolites (MPA 7-O-glucuronide [MPAG] and MPA acyl-glucuronide [AcMPAG]) is characterized by a large interindividual and intraindividual variability, resulting in part from variability in glucuronidation (via uridine diphosphate-glucuronosyltransferase isoforms) and excretion via multidrug resistance-associated protein 2 (MRP2). It can be hypothesized that drugs interfering with glucuronidation and excretion will alter (Ac)MPA(G) exposure.


METHODS
This prospective, open-label, nonrandomized, controlled pharmacokinetic interaction study included 8 stable renal allograft recipients, all treated with mycophenolate mofetil. Rifampin (INN, rifampicin), administered once daily (600 mg/d) for 8 days, was used as the probe drug because of its known effects on both uridine diphosphate-glucuronosyltransferase activity and MRP2 transport capacity. A 12-hour pharmacokinetic time-concentration profile was assessed before rifampin administration was started, and this was repeated on the last day of rifampin administration. Total and free MPA, MPAG, and AcMPAG concentrations in plasma and urine were measured by use of HPLC with tandem mass spectrometry detection.


RESULTS
Total MPA area under the plasma concentration-time curve (AUC) from 0 to 12 hours decreased significantly after rifampin coadministration (17.5% decrease [95% confidence interval (CI), 5.18%-29.9%]; P=.0234). This was mainly a result of a decrease in total MPA AUC from 6 to 12 hours (32.9% decrease [95% CI, 15.4%-50.4%]; P=.0078), representing decreased enterohepatic recirculation. Free MPA AUC from 6 to 12 hours decreased significantly, by 22.4% (95% CI, 4.71%-49.5%; P=.0391). Total MPAG and AcMPAG AUC from 0 to 12 hours increased by 34.4% (95% CI, 13.5%-55.4%; P=.0156) and 193% (95% CI, 30.3%-355%; P=.0078) respectively. Urinary recovery of MPAG and AcMPAG increased significantly (P=.0078), but renal clearance of these glucuronides did not change after rifampin coadministration.


CONCLUSIONS
This study demonstrates an interaction between mycophenolate mofetil and rifampin, which is a result of induction of MPA glucuronidation and possibly also rifampin-associated alterations in MRP2-mediated transport of MPAG and AcMPAG. This interaction should be taken into account when rifampin or other drugs influencing pregnane X receptor activity are coadministered with mycophenolate mofetil.
Naesens
Maarten
M
Department of Nephrology, Catholic University Leuven, University Hospitals Leuven, Belgium.
Kuypers
Dirk R J
DR
Streit
Frank
F
Armstrong
Victor W
VW
Oellerich
Michael
M
Verbeke
Kristin
K
Vanrenterghem
Yves
Y
D000328:Adult; D000368:Aged; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000494:pharmacology; D019540:Area Under Curve; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D020719:Glucuronides / Q000097:blood / Q000378:metabolism / Q000652:urine; D014453:Glucuronosyltransferase / Q000235:genetics; D006720:Homozygote; D006801:Humans; D016030:Kidney Transplantation; D026901:Membrane Transport Proteins / Q000235:genetics; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D016133:Polymerase Chain Reaction / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D014184:Transplantation, Homologous; D000090264:UDP-Glucuronosyltransferase 1A9
D000904:Antibiotics, Antitubercular; D004791:Enzyme Inhibitors; D020719:Glucuronides; D014453:Glucuronosyltransferase; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; D012293:Rifampin; D000090264:UDP-Glucuronosyltransferase 1A9; C000715087:ABCC2 protein, human; C113145:mycophenolic acid glucuronide