Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice

Table 1

Plasma pharmacokinetics and PBPK modelling results based on [¹¹C]AM7 and [¹¹C]MT107 PET data.

	[^11C]AM7		[^11C]MT107
	Control	Cyclosporine	Control	Cyclosporine
Body weight (g)	24.4/19.7	25.3	19.0 ± 2.4	20.2 ± 1.1
Plasma kinetics (Equation (1))
(ml)	3.0/2.3	4.2	1.49 ± 0.19	1.38 ± 0.11
(ml)	10.3/9.4	8.0	2.66 ± 0.51	3.33 ± 0.80
(1/min)	0.196/0.295	0.204	0.121 ± 0.011	0.139 ± 0.021
(1/min)	0.0234/0.0270	0.0206	0.0210 ± 0.0011	0.0140 ± 0.0034
CL (µl/min)	242/253	165	56.1 ± 13.0	45.0 ± 10.1
In vivo PBPK modelling
(µl/min)	103 (18.3%)/120 (5.8%)	n.d.	35.2 ± 10.9	17.1 ± 5.6
(-)		n.d.	0.035 ± 0.011	0.017 ± 0.006
(µl/min)	161/179	n.d.	11.9 ± 5.3	19.9 ± 5.1
/GFR (-)	1.0/1.1	n.d.	0.074 ± 0.033	0.12 ± 0.03
/ (-)	0.64/0.63	n.d.	3.8 ± 3.0	0.9 ± 0.2
CL (µl/min)	264/298	n.d.	47.1 ± 11.9	37.0 ± 8.9
(-)	0.11/0.12	n.d.	0.10 ± 0.02	0.14 ± 0.03

PBPK parameters were calculated from the fitted k according to (2) and (3) and the model in Figure 2. values for [¹¹C]AM7 and mean with standard deviations for [¹¹C]MT107; n, number of scans; decrease compared to [¹¹C]MT107 control; [¹¹C]AM7, includes × (% contribution shown in brackets; see Figure 2) , not determined; ratios > 2.0; ratios < 1.1. ; .