A short-term high fat diet increases exposure to midazolam and omeprazole in healthy subjects

Figures & data

Table 1. Gradient profile of HPLC mobile phase.

Step	Time (min)	Ultrapure water (%)	Acetonitrile (%)	2% Acetic acid/2% ammonium formate in water (%)	Flow (ml min^−1)
0	0.00	93.0	2.0	5.0	0.4
1	4.00	5.0	90.0	5.0	0.4
2	4.01	90.0	2.0	5.0	0.4
3	5.00	90.0	2.0	5.0	0.4

Table 2. Mass transition monitored for each probe and its internal standard.

Drug	Transition monitored	IS name	Transition monitored
Caffeine	194.85 → 138.00	Caffeine-D9	204.25 → 144.15
Metoprolol	268.05 → 191.00	Metoprolol-D7	275.25 → 191.10
Omeprazole	345.85 → 197.95	Omeprazole-D3	349.15 → 198.05
Midazolam	326.10 → 291.1	Midazolam-D5	331.1 → 296.1
R- and S-warfarin	307.00 → 160.85	Warfarin-D5	312.10 → 160.85

Table 3. Effects of 3 days of a high-fat diet versus control diet on biochemical parameters in healthy men after an overnight fast.

	Control visit Median [range]	High-fat diet Median [range]	p Value
Glucose (mmol l^−l)	5.1 [4.65–5.45]	5.1 [4.95–5.35]	0.78
β-Hydroxybutyrate (mmol l^−1)	0.1 [0.0–0.15]	0.0 [0.0–0.1]	0.08
Acetoacetate (mmol l^−1) (N = 8)	0.03 [0.02–0.08]	0.03 [0.02–0.04]	0.21
Triglycerides (mmol l^−1)	0.82 [0.57–1.42]	1.18 [0.79–1.88]	0.11
Free fatty acids (mmol l^−1) (N = 7)	0.50 [0.28–0.70]	0.37 [0.21–0.48]	0.17
C-Reactive protein (mg l^−1)	0.4 [0.3–0.65]	0.5 [0.3–1.35]	0.55

Table 4. Pharmacokinetic parameters (mean [95% CI]) of cocktail substances after control diet and after a high-fat diet.

	Control	High fat	p Value
Midazolam
AUC0–>t (ng ml^−1 h^−1)	22.5 (17.6–27.4)	26.6 (20.5–32.7)	0.07
AUC0–>inf (ng ml^−1 h^−1)	24.7 (19.6–29.8)	29.5 (22.4–36.6)	0.04
t1/2 (h)	2.6 (2.2–3.0)	2.7 (2.5–2.9)	0.37
Cmax (ng ml^−1)	9.2 (7.4–11.0)	10.0 (7.8–12.2)	0.59
Tmax (h)	0.99 (0.92–1.06)	0.99 (0.94–1.04)	0.95
Vd/F (l)	323 (239–407)	329 (266–392)	0.68
Cl/F (l h^−1)	103 (81.8–124.2)	88.8 (67.2–110.4)	0.04
Omeprazole
AUC0–>t (ng ml^−1 h^−1)	721 (517–925)	947 (618–1276)	0.05
AUC0–>inf (ng ml^−1 h^−1)	726 (522–930)	951 (622–1280)	0.05
t1/2 (h)	0.9 (0.8–1.0)	0.9 (0.8–1.0)	0.52
Cmax (ng ml^−1)	315 (217–413)	544 (332–756)	0.03
Tmax (h)	2.00 (1.95–2.05)	1.68 (1.38–1.98)	0.52
Vd/F (l)	45.5 (26.9–64.1)	34.1 (22.9–45.3)	0.11
Cl/F (l h^−1)	32.5 (23.3–41.7)	28.9 (16.7–41.1)	0.31
Caffeine
AUC0–>t (ng ml^−1 h^−1)	11,689 (10,121–13,257)	10,741 (9408–12074)	0.33
AUC0–>inf (ng ml^−1 h^−1)	17,615 (13,971–21,259)	14,370 (12,073–16,667)	0.16
t1/2 (h)	5.7 (4.9–6.5)	4.5 (3.9–5.1)	0.07
Cmax (ng ml^−1)	1971 (1812–2130)	1965 (1720–2210)	0.89
Tmax (h)	0.99 (0.92–1.06)	1.11 (0.90–1.32)	0.59
Vd/F (l)	47.7 (44.6–50.8)	47.4 (42.0–52.8)	0.89
Cl/F (l h^−1)	6.3 (4.9–7.7)	7.4 (6.0–8.8)	0.26
Metoprolol
AUC0–>t (ng ml^−1 h^−1)	1268 (488–2048)	884 (229–1539)	0.31
AUC0–>inf (ng ml^−1 h^−1)	1294 (510–2078)	940 (285–1595)	0.44
t1/2 (h)	4.1 (2.7–5.5)	3.6 (2.4–4.8)	0.17
Cmax (ng ml^−1)	230 (154–306)	170 (115–225)	0.21
Tmax (h)	1.45 (1.05–1.85)	1.23 (0.92–1.54)	0.44
Vd/F (l)	653 (459–847)	827 (525–1129)	0.17
Cl/F (l h^−1)	157 (70–244)	223 (81–365)	0.21
S-warfarin
AUC0–>t (ng ml^−1 h^−1)	13,097 (11,370–14,824)	12,838 (11,017–14,659)	0.59
AUC0–>inf (ng ml^−1 h^−1)	14,110 (12,093–16,127)	13,893 (12,041–15,745)	0.86
t1/2 (h)	76.3 (66.9–85.7)	82.3 (70.5–94.1)	0.09
Cmax (ng ml^−1)	265 (243–287)	249 (225–273)	0.26
Tmax (h)	0.99 (0.92–1.06)	0.99 (0.94–1.04)	0.95
Vd/F (l)	20.0 (17.2–22.7)	21.7 (19.0–24.4)	0.21
Cl/F (l h^−1)	0.19 (0.17–0.21)	0.19 (0.17–0.21)	0.95

Figure 1. Mean (95% confidence interval) plasma concentration versus time plots for each individual drug after the high fat diet versus the control diet.