TABLE 4.

Experimentally observed and simulated alteration of TCA total concentration in Cells (C_t,Cells) due to telmisartan and bosentan

Observed data are presented as fold change in the presence compared with the absence of inhibitors. SCHH were pretreated with telmisartan (1 and 10 µM) or bosentan (0.8 and 8 µM) for 10 min, followed by coincubation with d₈-TCA and telmisartan or bosentan for 10 min. Observed data represented arithmetic mean (range) measured in n = 1 SCHH preparation in duplicate. Monte Carlo simulations for 40 individuals were performed 10 times using parameter estimates and associated variance (Table 2), different inhibitor concentrations (Table 3), and IC₅₀ data (Table 1) assuming CL_Uptake was mediated by NTCP (70%) and OATPs (30%), CL_Bile was mediated by BSEP, and CL_BL was governed by MRP3. Simulation data are presented as arithmetic mean of 10 simulations (95% confidence interval). Average fold errors were calculated based on eq. 11.

Inhibitor	Dosing Concentration	Fold Change in TCA Ct,Cells
		Observation	Simulation
			[I]t,cell	[I]u,cell	[I]t,cyt	[I]u,cyt
Telmisartan	1 µM	0.91 (0.87–0.95)	1.3 (1.3–1.4)	1.0 (0.99–1.1)	1.3 (1.3–1.3)	1.0 (0.94–1.1)
	10 µM	1.1 (1.0–1.1)	1.4 (1.3–1.4)	1.0 (0.98–1.0)	1.3 (1.3–1.3)	0.96 (0.95–0.98)
	Average fold error		1.4	1.0	1.3	0.99
Bosentan	0.8 µM	0.88 (0.83–0.92)	1.0 (0.99–1.0)	0.99 (0.96–1.0)	1.0 (0.99–1.0)	0.99 (0.97–1.0)
	8 µM	0.81 (0.80–0.82)	1.2 (1.2–1.3)	1.0 (1.0–1.1)	1.1 (1.1–1.2)	N/A
	Average fold error		1.3	1.2	1.3	N/A

N/A, not available.