Table 1

Tissue levels of radioactivity (nanograms per gram of tissue) in wild-type and mdr1a(−/−) mice at 2 h after i.v. injection of [¹⁴C]nelfinavir (5 mg/kg)

	Plasma	Brain	Brain/Plasma Ratio	Testes	Testes/Plasma Ratio
mdr1a(−/−) mice
Vehicle	89 ± 15	184 ± 20^***	2.3 ± 0.24^**	194 ± 34^**	2.1 ± 0.35^***
Valspodar (50 mg/kg)	1730 ± 266^***	666 ± 174^**	0.38 ± 0.08^***	329 ± 51^***	0.19 ± 0.01^***
LY-335979 (50 mg/kg)	161 ± 24^**	318 ± 52^***	1.9 ± 0.12^***	207 ± 46^**	1.3 ± 0.13
mdr1a(+/+) mice
LY-335979
Vehicle control	84 ± 4.9	6.6 ± 1.7	0.08 ± 0.02	47 ± 3.7	0.48 ± 0.07
1 mg/kg	74 ± 14	9.4 ± 1.7	0.11 ± 0.04	56 ± 1.7	0.81 ± 0.13^*
4 mg/kg	72 ± 4.8	24 ± 4.5^***	0.33 ± 0.04^***	95 ± 18^*	1.4 ± 0.33^**
12.5 mg/kg	71 ± 11	60 ± 5.4^***	0.89 ± 0.16^***	108 ± 27^*	1.6 ± 0.44^*
25 mg/kg	89 ± 8.1	89 ± 17^***	1.1 ± 0.28^**	168 ± 61^*	2.0 ± 0.48^**
50 mg/kg	171 ± 12^***	243 ± 19^***	1.4 ± 0.08^***	187 ± 17^***	1.2 ± 0.19^**
Valspodar
1 mg/kg	92 ± 2.8	5.9 ± 2.6	0.07 ± 0.03	49 ± 5.6	0.53 ± 0.05
4 mg/kg	169 ± 22^*	46 ± 21	0.25 ± 0.08	156 ± 26^*	0.78 ± 0.16
12.5 mg/kg	405 ± 57^***	398 ± 118^*	0.92 ± 0.15^***	309 ± 86^*	0.74 ± 0.14
25 mg/kg	872 ± 121^***	546 ± 145^**	0.55 ± 0.13^**	274 ± 40^***	0.28 ± 0.04
50 mg/kg	1774 ± 263^***	652 ± 78^***	0.38 ± 0.04^**	406 ± 48^***	0.25 ± 0.02
Cyclosporine
Vehicle control	103 ± 13	9.2 ± 1.2	0.10 ± 0.03	66 ± 12	0.42 ± 0.04
1 mg/kg	120 ± 6.0	11 ± 2.4	0.10 ± 0.02	61 ± 7.0	0.51 ± 0.04
4 mg/kg	322 ± 14^***	45 ± 20^*	0.13 ± 0.06	128 ± 10^***	0.40 ± 0.05
12.5 mg/kg	698 ± 189^**	89 ± 19^**	0.18 ± 0.08	195 ± 54^*	0.30 ± 0.07
25 mg/kg	659 ± 57^***	190 ± 43^***	0.30 ± 0.08^*	294 ± 50^***	0.44 ± 0.04
50 mg/kg	954 ± 132^***	242 ± 46^***	0.27 ± 0.07^*	245 ± 55^**	0.25 ± 0.07
Vehicle control	99 ± 6.7	9.4 ± 3.0	0.10 ± 0.02	41 ± 6.8	0.38 ± 0.06
Quinidine (50 mg/kg)	92 ± 2.5	5.1 ± 1.5	0.06 ± 0.01	47 ± 7.3	0.54 ± 0.06
Verapamil (12.5 mg)	91 ± 6.1	8.4 ± 2.1	0.09 ± 0.02	39 ± 3.0	0.44 ± 0.06
Ketoconazole (50 mg/kg)	292 ± 68^*	57 ± 14^**	0.20 ± 0.02^*	87 ± 16^*	0.30 ± 0.04
Vehicle control	98 ± 12	5.1 ± 1.9	0.06 ± 0.01	31 ± 5.8	0.29 ± 0.02
Ritonavir (25 mg/kg)	618 ± 112^***	22 ± 3.8^**	0.08 ± 0.05	59 ± 3.4	0.31 ± 0.14
Nelfinavir (50 mg/kg)	124 ± 11	7.9 ± 1.5	0.06 ± 0.02	47 ± 6.6	0.39 ± 0.07
Saquinavir (50 mg/kg)	117 ± 14	6.9 ± 1.9	0.06 ± 0.01	48 ± 11	0.43 ± 0.13
Indinavir (50 mg/kg)	100 ± 6.2	7.5 ± 0.9	0.08 ± 0.01	37 ± 8.1	0.39 ± 0.05

Mice were treated with varying doses of LY-335979 or other known P-gp inhibitors (50 mg/kg, unless noted otherwise) in two divided doses, given 30 min before and simultaneously with [¹⁴C]nelfinavir. Data are shown as mean ± S.E. Statistical difference in radioactivity between the two groups of mice (3–5 per group), relative to vehicle control in each group, was assessed using a two-sided Student's t test, with P < .05 as the limit of significance (^* P < .05,^** P < .01, ^*** P < .001).