Piperine Alters the Pharmacokinetics and Anticoagulation of Warfarin in Rats

Figures & data

Table 1 Pharmacokinetics of Warfarin (2 mg/kg, p.o.) After Co-Administration of Piperine (20 mg/kg), Sulfaphenazole (120 mg/kg) and Ketoconazole (30 mg/kg)

Pharmacokinetic Parameters	Warfarin Alone	Warfarin + Piperine	Warfarin + Sulfaphenazole	Warfarin + Ketoconazole
Cmax (ng/mL)	16,125 2421	11,0041894	17,601 4049	28,013 1949^b
Tmax (h)	3.0 0.56	5.00.42	7.0 0.58^b	7.0  0.80^b
AUC0–∞ (ng.h/mL)	378,353 66,632	302,54137733	482,900 93,770	606,66036819^a
MRT (h)	27.0 5.00	29.8 2.00	19.61.0	17.01.0
CL/F (mL/h/kg)	6.0 0.87	7.3 1.20	4.5 0.6	3.30.2
Vd/F (mL/kg)	292 64	397178	81 12	827.3
t 1/2 (h)	32.55.00	31.6 7.50	12.00.6	16.8 0.7

Notes: ^ap<0.05. ^bp<0.01. Data shown are mean ± SEM (n=6). Numbers in bold font indicate significant difference.

Table 2 Pharmacokinetics of 7-Hydroxywarfarin After Co-Administration of Piperine (20 mg/kg), Sulfaphenazole (120 mg/kg) and Ketoconazole (30 mg/kg)

Pharmacokinetic Parameters	Warfarin Alone	Warfarin + Piperine	Warfarin + Sulfaphenazole	Warfarin + Ketoconazole
Cmax (ng/mL)	36564	457.2^c	17338^a	24731
Tmax (h)	7.00.66	14 4.0	26 1.5^b	12 4.0
AUC0–∞, (ng.h/mL)	10,3431858	1752187^c	5497 1348^a	5516373^a
MRT (h)	334.00	354.00	241.00	182.00
CL/F (mL/h/kg)	22335	1213136^c	41569	36826
Vd/F (mL/kg)	64091832	37,791 8429^c	3703507	3872 367
t 1/2 (h)	216.0	21 3.0	6.7 1.3	7.0 0.5

Notes: ^ap<0.05. ^bp<0.01. ^cp<0.001. Data shown are mean ± SEM (n=6). Numbers in bold font indicate significant difference.

Figure 1 The plasma mean concentration versus time profiles of warfarin determined after administration of a single oral dose of warfarin alone (2 mg/kg), warfarin (2 mg/kg) with piperine (20 mg/kg, p.o.), warfarin (2 mg/kg) with sulfaphenazole (120 mg/kg, p.o.), and warfarin (2 mg/kg) with ketoconazole (30 mg/kg, p.o.) in Sprague-Dawley rats. Data are shown in mean ± SEM, n=6.

Figure 2 The plasma mean concentration versus time profiles of 7-hydroxywarfarin determined after administration of a single oral dose of warfarin alone (2 mg/kg), warfarin (2 mg/kg) with piperine (20 mg/kg, p.o.), warfarin (2 mg/kg) with sulfaphenazole (120 mg/kg, p.o.), and warfarin (2 mg/kg) with ketoconazole (30 mg/kg, p.o.) in Sprague-Dawley rats. Data are shown in mean ± SEM, n=6.

Figure 3 Relative formation of 7-hydroxywarfarin to warfarin, calculated as AUC_{7-hydroxywarfarin}/AUC_warfarin, after administration of a single oral dose of warfarin alone (2 mg/kg), warfarin (2 mg/kg) with piperine (20 mg/kg, p.o.), warfarin (2 mg/kg) with sulfaphenazole (120 mg/kg, p.o.), and warfarin (2 mg/kg) with ketoconazole (30 mg/kg, p.o.) in Sprague-Dawley rats. Data are shown in mean ± SEM. *p<0.05, **p<0.01.

Figure 4 Comparison of INR values for warfarin between different rat groups following a single oral dose of warfarin alone (2 mg/kg), warfarin (2 mg/kg) with piperine (20 mg/kg, p.o.), warfarin (2 mg/kg) with sulfaphenazole (120 mg/kg, p.o.), and warfarin (2 mg/kg) with ketoconazole (30 mg/kg, p.o.). Data are shown in mean ± SEM, n=6. *p<0.05.