TABLE 1

IVIVE of fexofenadine, ipratropium, and rosuvastatin in vivo CL_hepatic

	Hepatocyte CL_int,uptake		Predicted CL_hepatic^{^a}		In vivo CL_hepatic^{^b}	In vivo CL_blood^{^c}
	Fresh	Cryopreserved	Fresh	Cryopreserved
	μl/min/10⁶ cells		ml/min/kg		ml/min/kg	ml/min/kg
Human (hepatocyte suspension)
Fexofenadine	11.4 ± 2.4	1.9^{^d}	4.2 ± 1.6	1.5	2.2	3.3
Rosuvastatin	21.2 ± 3.7	5.0 ± 1.3***	3.5 ± 0.7	1.2 ± 0.4	9.8	13.9
Ipratropium	25 ± 6	14.5 ± 3	12.4 ± 2.8	9.6 ± 2.1	19.5	31.4
Human (plated hepatocytes)
Fexofenadine	8.9 ± 3.4	0.8 ± 0.5***	3.4 ± 1.4	0.4 ± 0.2	2.2	3.3
Rosuvastatin	16.5 ± 2.1	3.9 ± 1.1***	2.3 ± 0.8	0.6 ± 0.2	9.8	13.9
Ipratropium	18.3 ± 2.7	11.2 ± 2.3*	11.1 ± 2	8.3 ± 2.6	19.5	31.4

Rat (hepatocyte suspension)
Fexofenadine	6 ± 1	2 ± 0.5**	4.8 ± 1.2	1.5 ± 0.6	7.2	10.9 ± 3.4
Rosuvastatin	36.2 ± 5.7	11 ± 2.5***	14.3 ± 4.4	4.9 ± 1.6	50	62.8 ± 8.2
Ipratropium	53 ± 8.5	34 ± 6*	36.2 ± 5.3	30.3 ± 4.1	36.1	58.3
Rat (plated hepatocytes)
Fexofenadine	11.2 ± 3.1	3 ± 0.9***	12.9	4.2	7.2	10.9 ± 3.4
Rosuvastatin	40 ± 12	9 ± 1.5***	15.3	4.4	50	62.8 ± 8.2
Ipratropium	51 ± 11.1	28 ± 7.8*	37.1	29	36.1	58.3

Data represent mean 6 S.D.; n = 3. *P, 0.05; **P, 0.01; ***P, 0.001 vs. fresh hepatocytes.
↵a Predicted in vivo CL_hepatic was derived from CL_int,uptake and eqs. 6–8.
↵b In vivo unbound CL_hepatic was calculated from CL_blood and the hepatically cleared fraction, f_hepatic. Values for f_hepatic are from Ensing et al. (1989), Kamath et al. (2005), Kitamura et al. (2008), Swift et al. (2009), and Varma et al. (2009). For ipratropium, rat f_hepatic is unknown and the human value was used as a substitute (references are listed in Supplemental Material).
↵c In vivo unbound CL_blood was calculated from rat plasma CL using eqs. 8 and 9. Human CL_blood values are from Ensing et al. (1989), Swift et al. (2009), and Varma et al. (2009). Human and rat CL_blood for ipratropium were from Ensing et al. (1989) and Urso et al. (1991), respectively (references are listed in Supplemental Material).
↵d Fexofenadine uptake in human cryopreserved hepatocytes in suspension was below 2 μl/min/10⁶ cells, the LOQ of the assay. The CL_int,uptake value of 1.9 represents a hypothetical maximum uptake value used for comparative purposes.