TABLE 1

Uptake clearance of drugs by human kidney slices

Uptake clearance of drugs by human kidney slices was determined at 37°C at two (trace and excess) concentrations. Final concentrations of the drugs were as follows: 0.1 and 100 μM for rosuvastatin, pitavastatin, and valsartan; 0.1 and 500 μM for pravastatin; 0.01 and 100 μM for olmesartan; 0.1 and 1000 μM for PAH; 1 and 1000 μM for benzylpenicillin; and 10 and 1000 μM for trichlormethiazide. The uptake clearance was calculated by dividing the uptake volume at 15 min by the drug concentration in the incubation buffer. Each value represents the mean ± S.E. (n = 3 slices). Benzylpenicillin was used as the standard compound throughout the study for normalization of the uptake of the test drugs by different batches of kidney slices.

	Batch No.	Uptake of Test Drug			Normalized Value^{^a}	CL_{uptake, slice}^{^b}
	Batch No.	Tracer (T)	Excess (E)	T − E	Normalized Value^{^a}	CL_{uptake, slice}^{^b}
		ml/g kidney/15 min				ml · min⁻¹ · kg⁻¹
Rosuvastatin	1	8.02 ± 1.55	2.69 ± 0.06	5.33 ± 1.55	11.9	3.30
Pravastatin	2	2.86 ± 0.11	0.84 ± 0.05	2.02 ± 0.12	1.77 ± 0.13	0.447
	3	2.62 ± 0.31	0.76 ± 0.04	1.86 ± 0.31	1.68 ± 0.38
	4	2.15 ± 0.10	0.71 ± 0.03	1.43 ± 0.10	1.71 ± 0.27
	5	2.05 ± 0.40	1 ± 0.12	1.05 ± 0.42	1.29 ± 0.23
Pitavastatin	6	20.6 ± 1.36	15.3 ± 1.52	5.27 ± 2.04	2.55	0.957
	8	15.3 ± 2.34	11.8 ± 1.04	3.50 ± 2.56	4.36 ± 0.24
Valsartan	1	8.28 ± 1.06	2.34 ± 0.34	5.94 ± 1.11	13.3	2.38
	7	6.38 ± 1.88	3.34 ± 0.12	3.04 ± 1.89	3.88 ± 0.24
Olmesartan	6	16.0 ± 0.72	1.67 ± 0.11	14.3 ± 0.73	6.93 ± 0.66	3.13
	7	13.9 ± 1.59	1.65 ± 0.04	12.2 ± 1.59	15.6 ± 0.76
Trichlormethiazide	3	5.18 ± 0.79	2.12 ± 0.06	3.06 ± 0.79	2.77 ± 0.63	1.01
	4	6.72 ± 0.86	2.94 ± 0.33	3.78 ± 0.92	4.50 ± 0.71
PAH	2	2.24 ± 0.31	0.55 ± 0.01	1.69 ± 0.31	1.48 ± 0.11	0.482
	3	2.14 ± 0.22	0.60 ± 0.03	1.54 ± 0.22	1.40 ± 0.32
	4	1.63 ± 0.17	0.63 ± 0.00	1.00 ± 0.17	1.19 ± 0.19
	5	2.98 ± 0.36	0.74 ± 0.32	2.24 ± 0.49	2.75 ± 0.49
	6	4.98 ± 0.21	1.12 ± 0.06	3.86 ± 0.22	1.87 ± 0.18
Fexofenadine^{^c}		2.60 ± 0.29	0.91 ± 0.21	1.68 ± 0.36	1.25 ± 0.19	0.347
Methotrexate^{^d}		1.26	0.51	0.75	0.61	0.168
Benzylpenicillin	1	1.56^{^e}	0.74^{^e}	0.82^{^e}	1.72^{^f} ± 0.09	0.508
	2	2.70 ± 0.15	0.61 ± 0.02	2.09 ± 0.15
	3	2.71 ± 0.46	0.69 ± 0.07	2.02 ± 0.46
	4	2.21 ± 0.24	0.68 ± 0.00	1.54 ± 0.24
	5	2.00 ± 0.11	0.51 ± 0.24	1.49 ± 0.26
	6	4.26 ± 0.27	0.46 ± 0.23	3.79 ± 0.36
	7	2.17 ± 0.07	0.74 ± 0.02	1.43 ± 0.07
	8	2.31^{^e}	0.84^{^e}	1.47^{^e}

↵a Uptake of test drugs was corrected by the ratio of the saturable uptake of benzylpenicillin in the same batch of human kidney to the average value (1.83).
↵b Normalized uptake clearance were scaled up to the in vivo value per body weight using the following physiological scaling factor: 4.43 g kidney/kg b.wt. (Davies and Morris, 1993). Average values were used for the extrapolation for rosuvastatin, pravastatin, pitavastatin, valsartan, olmesartan, trichlormethiazide, and PAH.
↵c T − E of benzylpenicillin was 2.47 ml/g kidney/15 min (Matsushima et al., 2009).
↵d T − E of benzylpenicillin was 2.26 ml/g kidney/15 min (Nozaki et al., 2007b).
↵e Average value of two slices.
↵f Average value used for the normalization.