TABLE 4

Summary of input parameters for estimation of in vivo K_puu for bosentan and rifampicin

Compound	CL^a	CL_R^a	f_u,p^b	R_b^c	In Vivo CL_int,h	In Vivo CL_int,uptake^d	CL_int,uptake	CL_int,bile^e	CL_int,passive	CL_int,metab	SF_uptake	K_puu
	l/h	l/h			(ml/min/kg)	µl/min/10⁶cells	µl/min/10⁶cells	µl/min/10⁶cells	µl/min/10⁶cells	(µl/min/mg)
Bosentan	12.3	0.1	0.037	0.62	101	74.0	17.1	2.0	13.2	20^f	4.32	4
Bosentan multiple dose	22.1	0.1	0.037	0.62	234	74.0	17.1	2.0	13.2	400^g	4.32	0.6
Rifampicin	7.5	1.2	0.15	0.90	10.9	50.6	12.3	—	3.1	0.7	4.11	15.9
Rifampicin multiple dose	13	1.2	0.15	0.90	21.9	50.6	12.3	—	3.1	1.5^g	4.11	14.7

↵^a Plasma clearance (CL) and renal clearance (CL_R) following an intravenous dose of bosentan (Weber et al., 1996) or rifampicin (day 2 and day 9) (Loos et al., 1985). For the induced bosentan CL following 8 days of dosing, estimated to be 22.1 l/h based on a 1.8-fold change in oral clearance over 8 days of dosing with 200 mg of oral bosentan (Weber et al., 1999).
↵^b Plasma protein-binding values were reported previously for bosentan (Obach et al., 2008) and rifampicin (Varma et al., 2014).
↵^c The blood-to-plasma ratios (R_b) were reported previously (Varma et al., 2014).
↵^d The in vivo estimate of CL_int,uptake was calculated from the in vivo CL_int,h using the CL_int,passive, CL_int,bile, and CL_int,metab listed in the table.
↵^e CL_int,bile for bosentan was reported by Varma et al. (2014).
↵^f CL_int,metab for bosentan was reported by Varma et al. (2014).
↵^g CL_int,metab was calculated from the multiple-day bosentan and rifampicin in vivo CL_int,h, assuming CL_int, uptake, CL_int,bile, and CL_int,passive remained constant.