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Although metformin, a cationic agent for type II diabetes, shows its pharmacological effect in the liver, the drug is mainly eliminated into urine. The tissue selectivity based on the function of drug transporters is unclear. In the present study, the transport of metformin was examined using HEK293 cells transiently transfected with five human renal organic ion transporter cDNAs. Human OCT1 and OCT2, but not OAT1, OAT3 or OCT2-A, stimulated the uptake. A kinetic analysis of metformin transport demonstrated that the amount of plasmid cDNA for transfection was also important parameter to the quantitative elucidation of functional characteristics of transporters, and both human and rat OCT2 had about a 10- and 100-fold greater capacity to transport metformin than did OCT1, respectively. In male rats, the mRNA expression level of rOCT2 in the whole kidneys was 8-fold greater than that of rOCT1 in the whole liver. The in vivo distribution of metformin in rats revealed that the expression level of renal OCT2 was a key factor in the control of the concentrative accumulation of metformin in the kidney. These findings suggest that metformin is a superior substrate for renal OCT2 rather than hepatic OCT1, and renal OCT2 plays a dominant role for metformin pharmacokinetics.

Cross-linking of allergen specific IgE bound to the high affinity IgE receptor (Fc ⑀ RI) on the surface of mast cells with multivalent allergens results in the release of both preformed and newly generated mediators, and in the manifestation of allergic symptoms. The expression of Fc ⑀ RI, and the synthesis of IgE are therefore critical for the development of allergic diseases. In this study, we report that nasal mast cells (

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These results indicate that in recipients of LDLT, the pharmacokinetics of tacrolimus is influenced by flux via P-glycoprotein in the intestine during the first week; after that, it is mostly the hepatic metabolism that contributes to the excretion of tacrolimus, and carriers of the CYP3A5*1/*1 genotype require a high dose of tacrolimus to achieve the target concentration.

These results suggest that hOCT2, but not hOCT1, is responsible for the basolateral membrane transport of creatinine in the human kidney.

Proliferative activity of the anterior pituitary gland in 10 week-old male and female rats under normal conditions was investigated by counting mitotic figures and using single and double immunostaining of 5-bromo-2'-deoxyuridine (BrdU), proliferating cell nuclear antigen (PCNA), and six pituitary hormones. To determine which proliferative changes depend on the estrous cycle and circadian changes, respectively, six groups of female and two groups of male rats were studied at various times of day. Additionally, BrdU-incorporated cells were further classified by the six types of hormones they contained, or as immunonegative cells. Cell proliferative activity in the females fluctuated drastically with the highest activity in estrus and the lowest in diestrus. In the males, proliferative activity was at a relatively low level, and was similar to that in females in proestrus or early estrus, with the greater activity at night. Identified by their pituitary hormones, the distribution of the proliferating cells was almost the same in each sex, with prolactin (PRL) cells accounting for the highest proportion, followed by growth hormone (GH) cells, and adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH) cells. These percentages agreed well with previously reported levels of cell types among all pituitary cells of the rat. It is therefore suggested that the life span and cycle of rat pituitary cells does not differ among cell types. In another test, male and female rats were given BrdU continuously via an osmotic pump for 8 days to compare cell proliferative activity between sexes, exclusive of the influence of estrous cycle and circadian changes. In this way, we were able to demonstrate that the cumulative incorporation of BrdU in females was consistently twice as high as in males over a constant period of time, and to conclude that cell renewal occurs at a doubled rate in the pituitary of female rat.