The influence of Javanese turmeric (Curcuma xanthorrhiza) on the pharmacokinetics of warfarin in rats with single and multiple-dose studies

Figures & data

Figure 1. Plasma concentration curve of R-WF in control and treatment groups; closed cycle: control group-Pulvis Gum Arabicum (2% PGA); closed rectangle: FZ group – Fluconazole at a dose of 6 mg/kg BW. Closed diamond: CX-1 – CX extract at a dose of 6 mg/kg BW; closed triangle: CX-2 is CX extract at a dose of 30 mg/kg BW.

Figure 2. Plasma concentration curve of S-WF in control and treatment groups; closed cycle: control group-Pulvis Gum Arabicum (2% PGA); closed rectangle: FZ group – Fluconazole at a dose of 6 mg/kg BW. Closed diamond: CX-1 – CX extract at a dose of 6 mg/kg BW; closed triangle: CX-2 is CX extract at a dose of 30 mg/kg BW.

Table 1. The concentration of R- and S-WF in rats after concomitant administration with CX extract.

t (h)	R-WF Concentration (µg/mL), n = 6				S-WF Concentration (µg/mL), n = 6
	Control	FZ	CX-1	CX-2	Control	FZ	CX-1	CX-2
0.5	3.61 ± 1.10	4.83 ± 1.09	3.71 ± 1.00	4.81 ± 0.91	6.17 ± 2.40	7.45 ± 1.82	6.37 ± 2.50	7.71 ± 1.39
1	3.22 ± 1.03	4.21 ± 0.93	3.32 ± 0.93	3.83 ± 1.01	5.24 ± 2.20	6.20 ± 1.57	5.44 ± 2.30	5.85 ± 1.50
2	2.77 ± 0.94	3.94 ± 0.72	2.87 ± 0.84	3.38 ± 0.87	4.44 ± 2.00	5.65 ± 1.21	4.64 ± 2.10	5.14 ± 1.23
4	2.47 ± 0.77	3.66 ± 0.67	2.57 ± 0.67	2.79 ± 0.56	4.06 ± 1.78	5.31 ± 1.29	4.26 ± 1.88	4.49 ± 1.04
8	2.13 ± 0.69	3.40 ± 0.70	2.43 ± 0.59	2.51 ± 0.54	3.67 ± 1.34	4.94 ± 1.32	3.87 ± 1.44	3.94 ± 0.83
12	1.63 ± 0.46	2.58 ± 1.02	1.83 ± 0.36	2.01 ± 0.52	2.94 ± 1.04	4.15 ± 1.72	3.14 ± 1.14	3.44 ± 0.98
24	1.12 ± 0.25	2.28 ± 0.77	1.22 ± 0.15	1.31 ± 0.39	2.27 ± 0.65	4.06 ± 1.31	2.47 ± 0.75	2.49 ± 0.57
36	0.70 ± 0.34	1.45 ± 0.61	0.80 ± 0.24	1.26 ± 0.65	1.55 ± 0.56	2.92 ± 0.99	1.75 ± 0.66	2.44 ± 0.93
48	0.49 ± 0.26	1.16 ± 0.49	0.29 ± 0.16	0.80 ± 0.44	1.15 ± 0.31	2.29 ± 0.81	1.35 ± 0.41	1.80 ± 0.72
60	0.51 ± 0.29	0.86 ± 0.64	0.61 ± 0.19	0.71 ± 0.40	1.16 ± 0.60	2.02 ± 0.97	1.36 ± 0.70	1.49 ± 0.79
72	0.33 ± 0.22	0.96 ± 0.78	0.43 ± 0.12	0.59 ± 0.41	1.10 ± 0.53	1.72 ± 0.96	1.30 ± 0.63	1.29 ± 0.88

Control: 2% PGA; FZ: Fluconazole at a dose of 6 mg/kg BW. CX-1: CX extract at a dose of 6 mg/kg BW; CX-2: CX extract at a dose of 30 mg/kg BW. n: number sample (rat), values are presented as mean ± SD, SD: Standard Deviation.

Table 2. Pharmacokinetic parameters of R- and S-WF in rats after administration of CX extract concomitantly.

PK Parameter	Unit	R-WF				S-WF
		Control	FZ	CX-1	CX-2	Control	FZ	CX-1	CX-2
k	1/h	0.07	0.05	0.05	0.04*	0.04	0.04	0.09	0.03*
t1/2	h	16.03	20.51	13.86	19.77*	28.71	28.50	16.21	74.26*
V	L	0.04	0.02	0.02	0.03	0.06	0.02	0.02	0.01*
CL (*10^–3)	L/h	3.00	1.00	2.00	1.00*	2.50	0.60	1.10	0.30*
AUC 0-t	mg.h/L	33.78	78.23**	51.78	71.36**	33.43	142.65**	89.28*	159.27**
AUC 0-inf	mg.h/L	35.27	85.71**	52.59	77.54**	40.16	172.17**	93.48*	316.26**
MRT	H	22.00	29.30	16.90	28.40	39.62	40.63	22.88	104.19*
Vss	L	0.06	0.03	0.03	0.04	0.10	0.02	0.02	0.03

Control: 2% PGA; FZ: Fluconazole at a dose of 6 mg/kg BW. CX-1: CX extract at a dose of 6 mg/kg BW; CX-2: CX extract at a dose of 30 mg/kg BW; k is elimination rate constant (sentral compartment); t_1/2 is biological half-life; V is volume of distribution; CL is drug clearance; AUC_0-t is Area Under the Curve from zero to t last time of observation; AUC_0-inf is Area Under the Curve from zero to infinitive time (AUC total); MRT is Mean Residence Time; V_ss is volume of distribution in steady state.

*The difference is statistically significant at a level of p < 0.05; **The difference is statistically significant at a level of p < 0.01 (by Kruskall-Wallis method).

Figure 3. Plasma concentration curve of R-WF in control and treatment groups with multiple-dose administration; closed cycle: control group, Pulvis Gum Arabicum (2% PGA); closed rectangle: FZ group, Fluconazole at a dose of 6 mg/kg BW. Closed diamond: CX-1, CX extract at a dose of 6 mg/kg BW; closed triangle: CX-2, CX extract at a dose of 30 mg/kg BW. SD bar is not displayed in this figure.

Figure 4. Plasma concentration curve of S-WF in control and treatment groups with multiple-dose administration; closed cycle: control group, Pulvis Gum Arabicum (2% PGA); closed rectangle: FZ group, Fluconazole at a dose of 6 mg/kg BW. Closed diamond: CX-1, CX extract at a dose of 6 mg/kg BW; closed triangle: CX-2, CX extract at a dose of 30 mg/kg BW. SD bar is not displayed in this figure.

Table 3. The concentration of R- and S-WF in the four groups of rats from day of 1–11 using multiple-dose study.

t (day)	Control (µg/mL)		CX-1 (µg/mL)		CX-2 (µg/mL)		FZ (µg/mL)
	R-WF	S-WF	R-WF	S-WF	R-WF	S-WF	R-WF	S-WF
1	1.05	1.31	1.00	1.47	1.28	1.34	1.30	2.17
2	1.35	1.87	1.43	2.49	2.87	3.45	2.13	3.19
3	1.65	2.71	1.70	3.47	3.14	4.42	2.40	4.17
4	1.75	2.45	1.74	3.89	2.69	5.30	2.44	4.59
5	1.99	3.45	2.24	5.16	3.29	6.40	2.94	5.86
6	2.18	4.36	2.18	5.18	3.32	6.32	3.82	6.89
7	2.02	4.50	2.28	5.47	3.44	6.85	4.87	8.90
8	2.15	4.52	2.29	5.56	3.80	8.39	NA	NA
9	2.04	4.54	2.33	5.79	3.98	8.68	NA	NA
10	2.10	5.02	2.57	6.34	3.81	8.72	NA	NA
11	2.15	5.12	2.34	6.30	4.26	8.60	NA	NA

Control: 2% PGA; FZ: Fluconazole at a dose of 6 mg/kg BW. CX-1: CX extract at a dose of 6 mg/kg BW; CX-2: CX extract at a dose of 30 mg/kg BW. SD is not displayed in this table.

Table 4. The increase in concentration level (ICL) of R- and S-WF from the 7th to 9th day in all groups of rats after CX extract administering concomitantly in the multiple-dose study.

Group	Day-7		Day-9		ICL (%)
	R-WF	S-WF	R-WF	S-WF	R-WF	S-WF
Control	2.02	4.50	2.04	4.54	1.04	0.93
CX-1	2.28	5.47	2.33	5.77	2.02	5.47
CX-2	3.44	6.85	3.98	8.68	15.68*	26.64*
FZ	4.87	8.90	NA	NA	NA	NA

Control: 2% PGA; FZ: Fluconazole at a dose of 6 mg/kg BW. CX-1: CX extract at a dose of 6 mg/kg BW; CX-2: CX extract at a dose of 30 mg/kg BW; ICL: increase in concentration level from 7th to 9th-day observation. NA: not available. sample discontinuing because of major bleeding or died. SD is not displayed in this table.

*The difference is statistically significant at a level of p < 0.05 (by Kruskall-Wallis method).