The effects of ferulic acid on the pharmacokinetics of warfarin in rats after biliary drainage

Figures & data

Figure 1 Enterohepatic circulation (EHC), the circulation of bile acid after oral administration.

Notes: (1) Warfarin enters the gastrointestinal tract after oral administration; (2) warfarin in the gastrointestinal tract enters the liver via the portal vein; (3) some of the warfarin in the liver is secreted into the bile duct; (4) warfarin in the bile duct enters the gastrointestinal tract through the duodenum; and (5) warfarin in the gastrointestinal tract is reabsorbed and transported back to the liver for systemic circulation.

Figure 2 Representative MRM chromatograms of warfarin in rats.

Notes: (A) Blank plasma samples from healthy rats; (B) blank plasma samples spiked with warfarin and IS; (C) plasma from rats with biliary drainage after a single administration of warfarin; (D) plasma from healthy rats after a single administration of warfarin; (E) plasma from rats with biliary drainage after the administration of warfarin and ferulic acid; and (F) plasma from healthy rats after the administration of warfarin and ferulic acid.
Abbreviations: MRM, multiple-reaction monitoring; ES-TIC, electrospray – total ions chromatograph; IS, internal standard.

Figure 3 Ultraperformance liquid chromatography–tandem mass spectrometry spectra of warfarin and methyclothiazide.

Notes: Warfarin and methyclothiazide can be ionized under negative ionization conditions. (M–H)⁻ predominated and was used as the precursor ion to obtain the ion spectra. The most sensitive mass transitions for warfarin (A) were m/z 307.03→250.02 and for methyclothiazide (B; IS) were 357.81→321.89.
Abbreviation: IS, internal standard.

Table 1 The intraday and interday precision of warfarin in rat plasma samples

	Spiked concentration (ng/mL)	Intraday		Interday
		Measured (ng/mL)	RSD%	Measured (ng/mL)	RSD%
Warfarin	50	49.73±3.56	7.16	50.32±3.31	6.58
	500	507.76±46.5	9.16	489.66±38.7	7.90
	2,500	2,513.02±201.2	8.01	2,551.78±197.8	7.75

Abbreviation: RSD, relative standard deviation.

Table 2 The pharmacokinetic parameters of warfarin (mean ± SD, n=5)

Group	WN	WO	WFN	WFO
AUC0–t (ng/mL⋅min)	2,304,674.80±638,144.86	1,175,817.25±192,837.94a	1,919,361.85±243,763.82	1,224,894.50±413,691.34b
MRT0–t (minutes)	606.31±66.18	718.31±40.74c	685.20±62.08	606.13±52.15b,d
t1/2Z (minutes)	1,221.34±528.65	1,546.99±778.57	1,104.66±544.20	884.79±498.02
Tmax (minutes)	132±65.73	432±107.33a	432±262.91c	240±278.21
Cmax (ng/mL)	2,308.36±414.84	1,085.02±293.33a	2,030.68±272.57	1,429.50±321.17b

Notes:

a Compared with the WN group P<0.01.

b Compared with the WFN group P<0.05.

c Compared with the WN group P<0.05.

d Compared with the WO group P<0.01.

Abbreviations: WN, healthy rats after a single administration of warfarin; WO, rats with biliary drainage after a single administration of warfarin; WFN, healthy rats after the administration of warfarin and ferulic acid; WFO, rats with biliary drainage after the administration of warfarin and ferulic acid; AUC_0–t, area under the curve from 0 to time; C_max, peak plasma concentration; MRT_0–t, mean retention time; t_1/2Z, terminal halftime; T_max, time to C_max.

Figure 4 The mean ± SD plasma concentration–time curves for warfarin (n=5).

Notes: WN: healthy rats after a single administration of warfarin sodium (0.5 mg/kg); WO: rats with biliary drainage after a single administration of warfarin sodium (0.5 mg/kg); WFN: healthy rats after the administration of warfarin sodium and ferulic acid (0.5 mg/kg and 1.5 mg/kg, respectively); WFO: rats with biliary drainage after the administration of warfarin sodium and ferulic acid (0.5 mg/kg and 1.5 mg/kg, respectively).