TABLE 1

Loperamide and N-desmethyl-loperamide pharmacokinetic parameters

Data are means ± S.D. n = 3 to 6.

Parameter	Wild Type	Mdr1a KO	Bcrp KO	Mrp2 KO
Loperamide (1 mg/kg i.v.)
AUC_inf, ng · h/ml	131 ± 12	243 ± 85	161 ± 40	122 ± 53
CL, l · h⁻¹ · kg⁻¹	7.7 ± 0.7	4.5 ± 1.4^*	6.6 ± 1.8	10.0 ± 5.2
V_{D, SS}, l/kg	9.0 ± 1.4	7.9 ± 0.9	11.5 ± 3.9	21.2 ± 15.4
t_1/2, h	1.0 ± 0.1	1.5 ± 0.5	1.5 ± 0.1^*	1.1 ± 0.1
Loperamide (10 mg/kg p.o.)
AUC_inf, ng · h/ml	806 ± 397	3.5-fold↑^{^a}	980 ± 542	1020 ± 293
C_max, ng/ml	90 ± 33	226 ± 81^*	69 ± 45	60 ± 17
T_max, h	0.3 ± 0.1	0.8 ± 0.3^*	0.7 ± 0.7	0.4 ± 0.1
t_1/2, h	13 ± 11	N.A.	15 ± 7	13 ± 7
F, %	43 ± 18	2.2-fold↑^*^{,^b}	40 ± 15	60 ± 17
N-Desmethyl-loperamide (10 mg/kg p.o. loperamide)
M/P	2.4 ± 0.9	55%↓^{^c}	3.3 ± 0.1	3.5 ± 0.7
AUC_inf, ng-eq · h/ml	1875 ± 932	1.5-fold↑^{^d}	3256 ± 1762	3658 ± 1587
C_max, ng-eq/ml	158 ± 59	193 ± 49	150 ± 48	109 ± 12
T_max, h	1.6 ± 1.4	2.2 ± 1.3	1.4 ± 0.8	10 ± 5
t_1/2, h	13 ± 13	N.A.	14 ± 7	24 ± 17

KO, knockout; AUC_inf, area under the curve extrapolated to infinity; CL, clearance; V_{D, SS}, volume of distribution; t_1/2, half-life; C_max, maximum concentration; T_max, time to maximum concentration; F, bioavailability; M/P, metabolite/parent ratio; N.A., not available.
↵* p < 0.05.
↵a Mdr1a KO rat oral loperamide exposure was measured only to 4 h, when Mdr1a KO rats became completely unresponsive. AUC_{0–4 h} was 651 ± 249 versus 184 ± 51 ng · h/ml in Mdr1a KO versus wild-type rats.
↵b Mdr1a KO rat bioavailability was estimated using oral and intravenous AUC_{0–4 h} values and was 34 ± 6 versus 16 ± 5% in Mdr1a KO versus wild-type rats.
↵c Mdr1a KO rat M/P ratio was estimated using AUC_{0–4 h} values and was 1.0 ± 0.2 versus 2.3 ± 0.3 in Mdr1a KO versus wild-type rats.
↵d Mdr1a KO rat N-desmethyl-loperamide exposure was measured only to 4 h when Mdr1a KO rats became completely unresponsive. AUC_{0–4 h} was 635 ± 151 versus 427 ± 156 ng-eq · h/ml in Mdr1a KO versus wild-type rats.