TABLE 2

Effect of selected compounds on SCr, CL_cr, and GFR in humans and the correlation with in vitro inhibition of OCT2, MATE1, and MATE2K

Inhibitors	Dosing Regimen	SCr ↑	CL_cr↓	GFR↓	Markers for GFR	C_max	f_u	C_max/IC₅₀^{^a}			C_max,u/IC₅₀^{^a}			References
Inhibitors	Dosing Regimen	SCr ↑	CL_cr↓	GFR↓	Markers for GFR	C_max	f_u	OCT2	MATE1	MATE2K	OCT2	MATE1	MATE2K
		%	%			μM
Cimetidine	400 mg (QDS)	13–26	20	NS	⁵¹Cr–EDTA,inulin	8–12	0.8	4.14	20.00	2.14	3.31	16.00	1.71	Dutt et al., 1981; Hilbrands et al., 1991
Pyrimethamine	50–100 mg SD	18–26	25–27	NS	inulin	2.3^{^a}	0.13	3.77	115.00	51.11	0.49	14.95	6.64	Opravil et al., 1993; Kusuhara et al., 2011
Famotidine	40 mg QD, 7days	NS	NS	—	—	0.39	0.8	0.02	0.87	0.06	0.01	0.69	0.05	Ishigami et al., 1989
Famotidine	200 mg SD; 160 mg q4h	SI	SI	—	—	1.25	0.8	0.06	2.78	0.19	0.05	2.22	0.15	Hibma et al., 2015
Ranitidine	300 mg QD	NS	NS	—	—	3.72	0.85	0.32	0.45	0.18	0.27	0.39	0.15	Motyl, 2004
Trimethoprim	20 mg/kg/day (10 days); 200 mg BID	31	16	NS	⁵¹Cr–EDTA iothalamate	3.4–6.9	0.56	0.35	13.53	49.29	0.20	7.58	27.60	Naderer et al., 1997; Arya et al., 2014
Dronedarone	400 mg BID 7days	10–15	18	NS	Sinistrin, PAH	0.30	0.02	0.16	0.65	0.03	0.003	0.013	0.001	Tschuppert et al., 2007
DX-619	800 mg (QD) (4 days)	30–40	26	NS	Iohexol	20.5–22	0.29–0.35^{^b}	23.40	26.83	220.0	8.19	9.39	77.0	Sarapa et al., 2007
Dolutegravir	50 mg (QD or BID, 14 days)	9–17	10 –14	NS	Iohexol Cystatin C	6.7–13.1	0.01	62.38	3.64	1.05	0.62	0.04	0.01	Koteff et al., 2013
Cobicistat	150 mg QD, 7 days, PO	10.5, 23	8–14, 9 – 20	NS	Iohexol	1.55	0.03	0.04	1.58	0.08	0.001	0.05	0.002	Cohen et al., 2011; German et al., 2012; Arya et al., 2014
Ritonavir	100 mg QD	—	25	NS	Iohexol	2.16	0.015	0.09	7.71	0.05	0.001	0.12	0.001	Deray et al., 1998; German et al., 2012; Lepist et al., 2014
Ranolazine	1000 mg BID, 5 days, PO	12	10	NS	Sinistrin	6.01	0.38	0.13	0.36	0.12	0.05	0.14	0.05	Arya et al., 2014
Rilpivirine	25 mg (QD, 96 weeks)	10	—	NS	Cystatin C	0.6	0.005	1.58	2.40	2.14	0.01	0.01	0.01	Drug label; Maggi et al., 2014
Amiodarone	400 mg QD	11	—	—	—	0.8–2.3	0.04	0.49	2.30	0.05	0.02	0.09	0.002	Pollak et al., 1993
Raltegravir	400 mg BID	NS	NS	—	—	3.38	0.17	<0.03	<0.03	<0.03	<0.01	<0.01	<0.01	Drug label; Maggi et al., 2014; Rizk et al., 2014
Telaprevir	750 mg q8h	SI	—	NS	Cystatin C, L–FABP, NAG	5.82	0.04–0.24^b	<0.06	0.09	<0.06	0.01	0.02	<0.01	Suzuki et al., 2013; Matsui et al., 2015
Vandetanib	300 mg QD	15	—	—	—	0.33	0.1	0.83	5.50	8.25	0.08	0.55	0.83	Shen et al., 2013

—, data are not reported or available; BID, twice daily; L-FABP, liver-type fatty acid binding protein; NAG, N-acetyl-β-Dglucosaminidase; NS, not significant (either statistically or clinically); PAH, para-amino-hippurate; PO, by mouth; QDS, four times a day; q4h, every 4 hours; q8h, every 8 hours; SD, single dose; SI, significantly increased compared with baseline level.
↵^a IC₅₀ values used were generated at Merck & Co. and shown in Table 1, except for DX-619, for which the lowest IC₅₀ value obtained from the literature is used (see Table 1).
↵^b Highest f_u values are used to estimate C_max,u/IC₅₀ as the worst-case scenario.