Table 1.
AUC ratios and metabolic ratios after administration of cocktail probe drugs with and without inhibitors and inducer
| CYP | Metric | Time (h) | Cocktail alone | Cocktail + inhibitors | Cocktail + inducer |
|---|---|---|---|---|---|
| 1A2 | AUC24par/AUC24caf | 0.63 (0.58–0.71) | 0.38 (0.35–0.45)*** | 0.64 (0.59–0.70)***a | |
| [par]/[caf] | 2 | 0.32 (0.29–0.38) | 0.13(0.11–0.20)***b | 0.38 (0.35–0.44)***a | |
| [par]/[caf] | 4 | 0.46 (0.41–0.55) | 0.21 (0.18–0.27)*** | 0.57 (0.52–0.64)***a | |
| [par]/[caf] | 6 | 0.64 (0.58–0.79) | 0.30 (0.26–0.38)***a | 0.78 (0.72–0.89)***a | |
| [par]/[caf] | 8 | 0.80 (0.71–0.97) | 0.39 (0.35–0.49)*** | 0.96 (0.87–1.13)***a | |
| 2B6 | AUC24efa/ AUC24OH-efa | 41.7 (37.9–48.2) | 73.9 (62.2–99.1)*** | 21.1 (19.7–23.2)***a | |
| [efa]/[OH-efa] | 2 | 23.7 (21.1–29.0) | 51.2 (43.3–70.0)***b | 12.8 (10.7–15.0)***a | |
| [efa]/[OH-efa] | 4 | 38.7 (34.8–48.5) | 84.1 (71.9–115.0)*** | 19.3 (17.9–21.3)***a | |
| [efa]/[OH-efa] | 6 | 43.7 (39.5–51.3) | 77.6 (69.3–94.2)***a | 23.1 (21.3–25.7)***a | |
| [efa]/[OH-efa] | 8 | 53.2 (47.8–62.6) | 88.7 (79.7–108.0)*** | 27.7 (26.0–30.8)***a | |
| 2C9 | AUClos/AUCE3174 | 0.09 (0.06–0.15) | 0.24 (0.19–0.41)*** | 0.07 (0.06–0.11)nsa | |
| [los]/[E3174] | 2 | 1.18 (1.17–2.99) | 3.39 (2.66–4.62)nsf | 0.44 (0.37–0.96)**b | |
| [los]/[E3174] | 4 | 0.17 (0.14–0.37) | 1.17 (1.03–2.09)*** | 0.08 (0.06–0.16)**a | |
| [los]/[E3174] | 6 | 0.10 (0.08–0.19) | 0.55 (0.47–1.01)***a | 0.06 (0.04–0.12)***c | |
| [los]/[E3174] | 8 | 0.05 (0.04–0.08) | 0.24 (0.20–0.42)*** | 0.05 (0.04–0.07) nsb | |
| 2C19 | AUCome/AUCOH-ome | 0.89 (0.76–1.17) | 17.9 (16.0–21.3)*** | 0.22 (0.19–0.30)***a | |
| [ome]/[OH-ome] | 2 | 1.08 (0.90–1.46) | 25.8 (22.7–33.2)*** | 0.25 (0.22–0.35)**a | |
| [ome]/[OH-ome] | 4 | 0.49 (0.38–0.86) | 18.1 (16.0–22.5)*** | 0.18 (0.15–0.24)***a | |
| [ome]/[OH-ome] | 6 | 0.28 (0.18–0.55)b | 14.6 (12.5–18.8)nta | na | |
| [ome]/[OH-ome] | 8 | na | na | na | |
| 2D6 | AUC24met/ AUC24OH-met | 1.69 (1.54–1.93) | 7.57 (5.48–10.89)*g | 1.45 (1.34–1.62)***b | |
| [met]/[OH-met] | 2 | 1.93 (1.56–2.47)e | na | 1.83 (1.60–2.18) ntd | |
| [met]/[OH-met] | 4 | 2.20 (2.00–2.54) | 6.60 (5.90–7.85)*** | 2.02 (1.84–2.31) nsa | |
| [met]/[OH-met] | 6 | 2.36 (2.16–2.69)a | 8.99 (8.33–10.01)*** | 1.88 (1.69–2.20)*a | |
| [met]/[OH-met] | 8 | 2.11 (1.91–2.44) | 9.90(9.06–11.39)*** | 1.67 (1.51–1.93) nsb | |
| 3A4 | AUCmid/AUC1-OH-mid | 1.55 (1.36–2.08) | 4.44 (3.92–5.67)*** | 3.89 (3.30–7.87)**a | |
| [mid]/[OH-mid] | 2 | 1.31 (1.16–1.77) | 3.46 (3.10–4.29)*** | 1.73 (1.54–2.11) nsa | |
| [mid]/[OH-mid] | 4 | 1.51 (1.33–1.97) | 3.81 (3.43–4.58)nt | na | |
| [mid]/[OH-mid] | 6 | 1.64 (1.35–2.31)c | 4.50 (3.94–5.60)nta | na | |
| [mid]/[OH-mid] | 8 | na | na | na | |
| 3A4 degluc | AUCmid/AUCOH-mid tot | 0.16 (0.14–0.21) | 0.61 (0.54–0.79)*** | 0.04 (0.03–0.05)***a | |
| [mid]/[OH-mid]tot | 2 | 0.17 (0.15–0.25) | 0.64 (0.56–0.85)*** | 0.06 (0.06–0.08)***a | |
| [mid]/[OH-mid]tot | 4 | 0.20 (0.18–0.27) | 0.67 (0.59–0.86)*** | 0.14 (0.06–0.23) nsh | |
| [mid]/[OH-mid]tot | 6 | 0.18 (0.15–0.26) | 0.65 (0.59–0.78)nta | na | |
| [mid]/[OH-mid]tot | 8 | na | na | na |
Data are presented as geometric mean ratios with 90 % confidence intervals
AUC area under plasma concentration-time curve from time 0 to last measurable concentration, AUC 24 area under the plasma concentration-time curve from time 0 to 24 h, caf caffeine, E3174 losartan carboxylic acid, efa efavirenz, los losartan, met metoprolol, mid midazolam, na not available, ns not significant, nt not tested, OH-efa 8-hydroxyefavirenz, OH-mid 1′-hydroxymidazolam, OH-mid tot total 1′-hydroxymidazolam concentration after deglucuronidation, OH-met α-hydroxymetoprolol, OH-ome 5-hydroxyomeprazole, par paraxanthine
* p < 0.025; ** p < 0.01; *** p < 0.001 (Wilcoxon signed rank test)
N = 16 unless indicated otherwise: a n = 15; b n = 14; c n = 13; d n = 10; e n = 8; f n = 7; g n = 6; h n = 3