Circadian pharmacokinetics of mycophenolic Acid and implication of genetic polymorphisms for early clinical events in renal transplant recipients.
BACKGROUND
We investigated the mycophenolic acid (MPA) chronopharmacokinetics and the relation between MPA circadian exposure and the incidence of acute rejection (AR). The association between selected genetic polymorphisms and clinical events or MPA circadian exposure was also studied.


METHODS
Thirty recipients were studied one month after renal transplantation. Mycophenolate mofetil (MMF) was administered twice a day at a single dose of 0.5 g in four patients, 0.75 g in eight patients, and 1 g in 18 patients.


RESULTS
The daytime area under the concentration-time curve (AUC0-12) was larger than the nighttime AUC0-12 (55.09 vs. 50.54 microg.hr/ml, P=0.049). The Cmax and tmax of MPA after the morning dose were respectively higher and shorter than those after the night dose. Seven patients (23.3%) had AR episodes. The MMF single dose per body weight (12.46 mg/kg in patients with AR vs. 16.99 in patients without AR), daytime and nighttime AUC0-12 (32.41 vs. 62.00 and 24.44 vs. 57.88 microg.hr/ml) and morning trough level of MPA (1.03 vs. 3.83 microg/ml) were significantly lower in patients with AR than in those without AR. The percentage of patients requiring diminished dose of MMF due to diarrhea was higher among patients with the multidrug resistance 1 (MDR1) C3435T T allele than among those with the CC genotype (P=0.049).


CONCLUSIONS
MPA pharmacokinetics showed circadian variations, and a lower MPA AUC in both daytime and nighttime was associated with the occurrence of AR in the early stage after renal transplantation. The MDR1 C3435T polymorphism might be associated with diarrhea due to MPA.
Satoh
Shigeru
S
Department of Urology, Akita University School of Medicine, Akita, Japan. shigerus@doc.med.akita-u.ac.jp
Tada
Hitoshi
H
Murakami
Miho
M
Tsuchiya
Norihiko
N
Li
Zhenhua
Z
Numakura
Kazuyuki
K
Saito
Mitsuru
M
Inoue
Tadamitsu
T
Miura
Masatomo
M
Hayase
Yukitoshi
Y
Suzuki
Toshio
T
Habuchi
Tomonori
T
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002940:Circadian Rhythm; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D019450:Genes, MDR; D014453:Glucuronosyltransferase / Q000235:genetics; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D000099148:UGT1A1 Enzyme
D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D000099148:UGT1A1 Enzyme; C510164:CYP3A5 protein, human