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Takekuma Y, Kakiuchi H, Yamazaki K, Miyauchi S, Kikukawa T, Kamo
N, Ganapathy V, Sugawara M. J Pharm Pharm Sci.
2007;10(1):71-85
Difference between pharmacokinetics of
mycophenolic acid (MPA) in rats and that in humans is caused by different
affinities of MRP2 to a glucuronized form.
Laboratory of Pharmcotherapeutic Information, Faculty of
Pharmaceutical Science, Hokkaido University, Sapporo, Japan.
y-kuma@pharm.hokudai.ac.jp
PURPOSE: Mycophenolic acid (MPA), an immunosuppressant, is
excreted as its glucuronized form, MPAG. In humans, MPAG is
mostly excreted into urine, whereas more than 80% of the dose is
excreted into bile in rats. The aim of this study was to clarify
the cause of the species difference. We investigated whether
MPAG is a substrate of human organic anion transporters (hOATs),
and we compared the affinities of multi-drug
resistance-associated protein 2 (MRP2) for MPAG in rats and
humans. METHODS: The inhibitory effects of MPAG on the uptake of
typical substrates via hOAT1 and hOAT3 were determined using
HeLa cells heterologously expressing hOAT1 and Xenopus laevis
oocytes heterologously expressing hOAT3. MPAG transport activity
via hOAT1 and hOAT3 was determined by the two-microelectrode
voltage-clamp technique using Xenopus laevis oocytes expressing
hOAT1 and hOAT3. The affinities of MPAG for hMRP2 and rMrp2 were
determined by the inhibitory effects of MPAG on p-aminohippuric
acid (a typical substrate) uptake using membrane vesicles
expressing hMRP2 or rMrp2. RESULTS: MPAG inhibited the uptake of
PAH via hOAT1 and hOAT3, and calculated IC50 values were
222.6+/-26.6 microM and 41.5+/-11.5 microM, respectively.
However, MPAG was not transported by hOAT1 and hOAT3. MPAG
strongly inhibited the uptake of PAH via both rMrp2 and hMRP2.
However, the magnitudes of inhibitory effects were different.
The calculated IC50 values were 286.2+/-157.3 microM and
1036.8+/-330.5 microM, respectively. CONCLUSION: MPAG is not a
substrate but is an inhibitor of hOAT1 and hOAT3. The affinity
of rMRP2 to MPAG was about 3.6 times as high as that of hMRP2.
Therefore, the difference of affinity between hMRP2 and rMrp2 is
a possible mechanism of the difference of excretion ratio of
MPAG between rats and human.
PMID: 17498396
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