The warfarin–cranberry juice interaction revisited: A systematic in vitro–in vivo evaluation

Figures & data

Figure 1 Inhibitory effects of different brands of cranberry juice, coded A–E, on the 7-hydroxylation of S-warfarin in human liver microsomes. Human liver microsomes (0.1 mg/mL) were incubated with S-warfarin (4 μM) and juice (0.05, 0.20, 0.50%, v/v) for 30 minutes. Reactions were initiated by the addition of NADPH (1 mM). S-warfarin 7-hydroxylation activity in the presence of vehicle control (water) was 5.7 ± 0.4 pmol/min/mg microsomal protein. Bars and error bars denote means and standard deviations, respectively, of triplicate incubations. ^*P < 0.05 versus 0.05% juice; ^#P < 0.05 versus 0.20% juice (one-way ANOVA, followed by Tukey’s test).

Figure 2 Inhibitory effects of the various fractions generated from the cranberry juice obtained from vendor A (A), B (B), C (C), D (D) and E (E) on the 7-hydroxylation of S-warfarin in human liver microsomes. Human liver microsomes (0.1 mg/mL) were incubated with S-warfarin (4 μM) and juice fraction (10 or 50 μg/mL) for 30 minutes. Reactions were initiated by the addition of NADPH (1 mM). S-warfarin 7-hydroxylation activity in the presence of vehicle control (1% methanol) was 2.3 ± 0.1 pmol/min/mg microsomal protein. Bars and error bars denote means and standard deviations, respectively, of triplicate incubations. ^*P < 0.05 versus 10 μg/mL; ^†P < 0.05 versus all other fractions at 10 μg/mL; ^‡P < 0.05 versus all other fractions at 50 μg/mL (two-way ANOVA, followed by Tukey’s test).

Abbreviations: Hex, hexane-soluble fraction; Chlor, chloroform-soluble fraction; BuOH, butanol-soluble fraction; Aq, aqueous-soluble fraction.

Figure 3 Geometric mean concentration-time profile (0–96 hours) of S-warfarin (A) and R-warfarin (B) for 16 healthy volunteers given three × 240 mL glasses of water or sweetened double-strength cranberry juice (CBJ) E and a single oral dose of warfarin (10 mg). Insets depict the 0–12-hour time profiles. Symbols and error bars denote geometric means and upper limits of the 90% confidence interval, respectively.

Figure 4 Effects of three × 240 mL glasses of water and sweetened double-strength cranberry juice (CBJ) E on the AUC_0–∞ (A) and terminal half-life (B) of S-warfarin in each of 16 healthy volunteers given a single oral dose of warfarin (10 mg). Open symbols connected by solid lines denote individual values. Filled symbols connected by dashed lines denote geometric mean values.

Table 1 Pharmacokinetics of S- and R-warfarin in 16 healthy volunteers given a single oral dose of warfarin (10 mg) with water or sweetened double-strength cranberry juice from vendor E (3 × 240 mL glasses).

Measure	Geometric mean (CV%)	CBJ/water ratio		P valuea
	Water	CBJ	[90% CI]
S-warfarin
tmax (h) [median (range)]	2.0 (0.5–4.0)	4.0 (3.0–8.0)	2.0b	<0.001
Cmax (μM)	2.0 (29)	1.5 (24)	0.73 [0.66–0.80]	<0.001
AUC0–∞ (μM * hour)	65 (30)	61 (29)	0.98 [0.89–1.07]	0.72
Cl/F (L/h)	0.25 (31)	0.27 (29)	1.02 [0.93–1.12]	0.72
t1/2 (h)	32 (26)	32 (24)	1.02 [0.94–1.12]	0.66
R-warfarin
tmax (h) [median (range)]	2.0 (0.5–12.0)	7.0 (3.0–12)	5.0b	<0.005
Cmax (μM)	1.7 (22)	1.4 (14)	0.82 [0.75–0.89]	<0.005
AUC0–∞ (μ M * hour)	93 (21)	95 (14)	1.03 [0.90–1.09]	0.47
Cl/F (L/h)	0.18 (21)	0.17 (14)	0.97 [0.92–1.03]	0.47
t1/2 (h)	42 (18)	42 (15)	0.79 [0.53–1.18]	0.91
S-to-R-warfarin ratios
Cmax,S-Warf/Cmax,R-Warf	1.17 (21)	1.04 (23)	0.89 [0.83–0.95]	<0.05
AUC0–∞,S-Warf/AUC0–∞,R-Warf	0.69 (30)	0.65 (32)	0.94 [0.89–0.99]	0.10

Notes:

a Comparisons between water and CBJ for t_max were made using the Wilcoxon signed-rank test; comparisons between water and CBJ for all other measures were made using the paired Student’s t-test;

b Median difference between water and CBJ.

Abbreviations: CBJ, cranberry juice; CI, confidence interval; t_max, time to reach maximum concentration (C_max); AUC_0–∞, area under the curve from 0 to infinite time; Cl/F, apparent oral clearance; t_1/2, terminal half-life.