The onset of diarrhea after the administration of mycophenolate mofetil (MMF) is possibly associated with the biliary excretion of its metabolite, mycophenolic acid glucuronide (MPAG). This study was undertaken to clarify the mechanism underlying the biliary excretion of MPAG. Intravenously administered mycophenolic acid (MPA, 5 mg/kg) rapidly disappeared from plasma and was efficiently excreted as MPAG in the bile of Wistar (26% of dose) and Sprague-Dawley rats (21% of dose) over 1 h. On the other hand, in spite of the rapid disappearance of MPA from plasma, the biliary excretion of MPAG was very limited in Eisai hyperbilirubinemic rats (EHBRs), which display mutations in multidrug resistance-associated protein 2 (Mrp2)/canalicular multispecific organic anion transporter, and constituted only 0.5% of dose. Instead, high levels of MPA were noted in the plasma of EHBRs. Intravenous administration of CsA (5 mg/kg) to Wistar rats significantly lowered the biliary excretion of MPAG. However, intravenously administered tacrolimus (0.1 mg/kg) failed to produce such effect. In conclusion, it is suggested that there is an efficient MPAG transport mediated by Mrp2 on the bile canalicular membrane of rat hepatocytes and that the therapeutic range of CsA potentially interferes with Mrp2. However, the therapeutic range of tacrolimus does not inhibit the transporter. Thus, it should be noted that MMF coadministered with tacrolimus instead of CsA might increase the occurrence of diarrhea related to the biliary excretion of MPAG in transplant recipients.

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ABSTRACT-Otsuka Long Evans Tokushima Fatty (OLETF) rats were developed as a model of noninsulin-dependent diabetes mellitus (NIDDM) with mild obesity. We reported that the daily profiles of energy expenditure associated with two peaks (one between 05:00 and 08:00 and the other between 20:00 and 22:00) were observed at 8 weeks of age (without NIDDM), while these two peaks disappeared at 24 weeks of age with NIDDM. As a new anti-diabetic drug, a peroxisome proliferator-activated receptor C agonist pioglitazone hydrochloride has been developed, we examined whether pioglitazone normalized daily profiles of energy expenditure at 24 weeks of age. A control diet and pioglitazone (0.1%)-containing diet were fed from 6 weeks of age. The two peaks of daily profiles of energy expenditure, which disappeared in OLETF rats with the control diet at 24 weeks of age, were reproduced by administration of pioglitazone. The respiratory quotient was lower and fat derived energy used for combustion was increased by pioglitazone at both ages. The body weight, daily food intake, plasma levels of fat, insulin, leptin and the wet weight of visceral fat were not influenced, but the levels of blood hemoglobin A1c and plasma tumor necrosis factor = were decreased by pioglitazone. Administration of pioglitazone improved daily profiles of energy expenditure via affecting glucose and fat metabolisms.Keywords: Energy expenditure, Non-insulin-dependent diabetes mellitus, Obesity, Peroxisome proliferator-activated receptor C Otsuka Long Evans Tokushima Fatty (OLETF) rats were developed as a model of non-insulin-dependent diabetes mellitus (NIDDM) with mild obesity (1). One mechanism of obesity in OLETF rats is disruption of the cholecystokinin (CCK)-A-receptor gene (2, 3). The CCK-A receptor has been implicated in satiety and a disrupted CCK-Areceptor gene induced hyperphagia (4). The characteristic features of OLETF rats are late onset of hyperglycemia at about 18 weeks of age, followed by insulin deficiency at about 65 weeks (1). In an original study by Kawano et al. 1992 (1), rats were divided to three groups after an oral glucose tolerance test (OGTT) was conducted. Glucose (2 g /kg) solution was given per os, and plasma levels of glucose were measured before and at 30, 60, 90 and 120 min: 1) Diabetic type rats had a peak level of plasma glucose >16.8 mM and a level of plasma glucose at 120 min >11.2 mM, and only rats that showed both conditions by OGTT were diagnosed with clinical DM; 2) if either of the two conditions was observed in the rats, they were diagnosed with impaired glucose tolerance (IGT); and 3) normal type, where neither DM nor IGT was present. After 23 weeks of age, OLETF rats with normal type parameters were not observed (94.7% with DM and 5.2% with IGT, respectively) (1).We have previously examined the daily profile of energy expenditure in OLETF and control [Long Evans Tokushima (LETO)] rats at 8 and 24 weeks of age (5, 6). The diurnal rhythm of energy expenditure associated with the highest and lowest values for energy co...