TABLE 3

Summary of clinical trials and estimated [I_,unbound]/K_i of P-gp inhibitors in humans

Dose and route of administration (substrates)	Inhibitor	Dose and route of administration (inhibitors)	Central nerve system end point	Inhibitor peak plasma concentration	Unbound fraction of inhibitor in human plasma	[I_,unbound] /K_i	Reference
Dose and route of administration (substrates)	Inhibitor	Dose and route of administration (inhibitors)	Central nerve system end point	μmol/l	Unbound fraction of inhibitor in human plasma	[I_,unbound] /K_i	Reference
Probe substrate: verapamil
379 ± 9 MBq of (R)-[¹¹C]verapamil i.v. administration	Tariquidar	8 mg/kg i.v. infusion for 30 min	3.3-fold increase of the influx rate constant	2.03	0.0063 ± 0.0021	1.28	(Bauer et al., 2012)
384 ± 13 MBq of (R)-[¹¹C]verapamil i.v. administration	Tariquidar	2 mg/kg i.v. infusion for 30 min	1.49-fold increase of the influx rate constant	0.76 ± 0.26	0.0063 ± 0.0021	0.48	(Wagner et al., 2009)
7.4 MBq/kg of [¹¹C]verapamil i.v. administration	Cyclosporin A	2.5 mg/kg/h i.v. infusion for 1 hour	1.88-fold increase of the AUC_,brain/ AUC_,blood ratio	2.80 ± 0.40	0.070 ± 0.020	0.44	(Sasongko et al., 2005)
7.4 MBq/kg of [¹¹C]verapamil i.v. administration	Cyclosporin A	2.5 mg/kg/h i.v. infusion for 1 hour	1.8-fold increase of the influx rate constant	2.80 ± 0.40	0.070 ± 0.020	0.44	(Eyal et al., 2010)
745 ± 16 MBq of (R)-[¹¹C]verapamil i.v. administration	Clarithromycin	400 mg/day oral administration (b.i.d. for 2 days)	None	2.00	0.44 ± 0.04	<0.01	(Arakawa et al., 2010)
Probe substrate: N-desmethyl loperamide
621-722 MBq of [¹¹C]N-desmethyl loperamide, i.v. administration	Tariquidar	6 mg/kg i.v. administration	3.7-fold increase of the influx rate constant	1.86	0.0063 ± 0.0021	1.17	(Kreisl et al., 2010)
Probe substrate: loperamide
343 ± 31 MBq of [¹¹C]loperamide i.v. administration	Quinidine	600 mg oral administration	1.33-fold increase of the influx rate constant	6.00	0.16 ± 0.03	1.17	(Passchier et al., 2008)
16 mg loperamide Single oral administration	Quinidine	600 mg oral administration	Respiratory depression	6.00	0.16 ± 0.03	1.17	(Sadeque et al., 2000)
32 mg loperamide Single oral administration	Tariquidar	150 mg/500 ml i.v. infusion for 30 min	None	0.64	0.0063 ± 0.0021	0.41	(Kurnik et al., 2008)
16 mg loperamide Single oral administration	Ketoconazole	400 mg oral administration	None	9.17	0.0071 ± 0.0017	0.07	(Fullerton et al., 2005)
16 mg loperamide Single oral administration	Saquinavir	600 mg oral administration	None	1.41	0.014 ± 0.004	<0.01	(Mikus et al., 2004)