. 2016 Apr 22;60(5):3096–3105. doi: 10.1128/AAC.02765-15

TABLE 3.

The drug-drug interaction index predicted from in vitro OATP1B1- and OATP2B1-mediated [³H]ES and OATP1B3-mediated [³H]E2G uptake inhibited by anti-TB drugs^a

Anti-TB drug	DDI index (R value = 1 + [I]/K_i) for:
	OATP1B1		OATP2B1		OATP1B3
	[I] = C_max	[I] = [I]_{u inlet,max}	[I] = C_max	[I] = [I]_{u inlet,max}	[I] = C_max	[I] = [I]_{u inlet,max}
PAS	13.70 ± 2.3*	26.1 ± 4.7*	ND	ND	26.70 ± 2.7*	51.90 ± 5.4*
Rifabutin	1.02 ± 0.002	1.10 ± 0.008	1.13 ± 0.002	1.04 ± 0.05	1.02 ± 0.001	1.10 ± 0.008
Ethambutol	1.39 ± 0.02	6.52 ± 0.28*	ND	ND	1.49 ± 0.20	8.00 ± 2.71*
Linezolid	1.84 ± 0.17	1.44 ± 0.08	2.54 ± 0.26*	4.43 ± 0.59*	1.87 ± 0.11	1.42 ± 0.05*
Amoxicillin	1.93 ± 0.06	4.33 ± 0.23*	1.58 ± 0.05	3.1 ± 0.18*	2.16 ± 0.17	4.67 ± 0.61*
Rifapentine	1.69 ± 0.12	1.06 ± 0.01	1.49 ± 0.05	1.02 ± 0.005	1.25 ± 0.03	1.0 ± 0.003
Rifampin	13.04 ± 0.34	6.6 ± 0.16*	1.26 ± 0.04	1.14 ± 0.02	4.59 ± 0.28	2.67 ± 0.13*
Amikacin	ND	ND	3.34 ± 0.39*	4.21 ± 0.55*	ND	ND
Kanamycin	ND	ND	1.58 ± 0.001	2.24 ± 0.5	ND	ND
Streptomycin	ND	ND	3.20 ± 0.13*	4.29 ± 0.24*	ND	ND
Roxithromycin	ND	ND	1.10 ± 0.007	1.02 ± 0.002	ND	ND
Clarithromycin	ND	ND	ND	ND	2.5 ± 0.22*	2.52 ± 0.21*
Clofazimine	ND	ND	1.15 ± 0.02	1.0 ± 0.001	1.15 ± 0.01	1.00 ± 0.001

The R values were determined using the inhibition constant, K_i, with the maximum systemic concentration, C_max (bound + unbound), of the anti-TB drugs as [I] and the maximum unbound concentration inlet to the liver, [I]_{u inlet,max}, following the regulatory guidelines described in the text. R values represent means ± SD obtained from the inhibition constants from three or more independent experiments. ND, not determined. *, statistically significant at P < 0.05. An asterisk indicates the result is significant according to FDA, MHLW, and EMA guidance for prototypical substrates in which the R values are greater than the corresponding cutoff values recommended by the regulatory authorities under both C_max (R ≥ 1.1, FDA) and [I]_{u inlet,max} (R ≥ 1.25, FDA and MHLW; R ≥ 1.04, EMA) conditions. The cutoff value is expressed as the suggested value according to the upper limit of the equivalence range by the FDA.