The effect of selective bowel decontamination on the pharmacokinetics of mycophenolate mofetil in liver transplant recipients.
Mycophenolate mofetil (MMF) is a prodrug immunosuppressant with a high oral bioavailability. Enterohepatic cycling of a glucuronide derivative of MMF contributes substantially to the bioavailability, but is dependent on bacterial deglucuronidation by intestinal flora. This study aims to determine whether an antibiotic regimen with activity against such organisms reduces the bioavailability of MMF by impairing enterohepatic cycling. In a prospective trial, 6 liver transplant recipients were administered MMF and a 21-day antibiotic regimen for selective bowel decontamination (SBD). Time-concentration profiles of the pharmacologically active metabolite, mycophenolic acid (MPA), were obtained during and after the SBD regimen. The bioavailability of MPA was reduced during compared with after the regimen (14.5 +/- 3.5 v 21.1 +/- 9.8 mg. h/mL; P =.07). The most pronounced contribution to this reduction was observed from 6 hours onward (2.4 +/- 1.4 v 5.6 +/- 4.4 mg. h/mL; P <.05). The presence of secondary maxima in the time-concentration profiles of MPA after, but not during, SBD indicates that enterohepatic cycling may be inhibited during SBD and restored afterward. Enterohepatic cycling may contribute 7% to 54% (mean, 29%) of the bioavailability of MPA. We conclude that the bioavailability of MMF may be reduced when SBD is used, and the reduction is likely to result from the interruption of enterohepatic cycling. This mechanism should be taken into consideration not only during SBD, but in any clinical setting combining MMF and broad-spectrum antibiotics.
Schmidt
L E
LE
Department of Hepatology A.2.12.1, Rigshospitalet, DK-2100 Copenhagen Ø, Denmark. lars.schmidt@dadlnet.dk
Rasmussen
A
A
Nørrelykke
M R
MR
Poulsen
H E
HE
Hansen
B A
BA
D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001682:Biological Availability; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D007422:Intestines / Q000187:drug effects* / Q000382:microbiology*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D011446:Prospective Studies; D013997:Time Factors
D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid