Table 3 Intravenous drug–drug interaction (DDI) studies of cytochrome P450 (CYP) index substrates

From: Volume of Distribution is Unaffected by Metabolic Drug–Drug Interactions

Victim Perpetrator Victim enzymes or transporters Perpetrator enzymes or transporters Population N \(\frac{{{\text{AUC}}^{\text{DDI}} }}{{{\text{AUC}}^{\text{Con}} }}\) \(\frac{{{\text{CL}}^{\text{DDI}} }}{{{\text{CL}}^{\text{Con}} }}\) \(\frac{{V_{\text{ss}}^{\text{DDI}} }}{{V_{\text{ss}}^{\text{Con}} }}\) \(\frac{{{\text{MRT}}^{\text{DDI}} }}{{{\text{MRT}}^{\text{Con}} }}\) \(\frac{{t_{1/2,z}^{\text{DDI}} }}{{t_{1/2,z}^{\text{Con}} }}\) Percent AUC extrapolation Refs.
Caffeine Ketoconazole (400 mg; single dose) CYP1A2
NAT
XO
CYP3A4
CYP2C19
P-gp
Healthy subjects 8 1.17b 0.88b 0.97a 1.14a 1.18b 36%/30%a [14]
Caffeine Terbinafine (500 mg; single dose) CYP1A2
NAT
XO
CYP2D6
CYP1A2
Healthy subjects 8 1.31b 0.81b 1.05a 1.48a 1.35b 45%/30%a [14]
Metoprolol Quinidine (50 mg; single dose) CYP2D6
CYP3A4
CYP2D6
P-gp
Healthy subjects; male, white, CYP2D6 extensive metabolizers 3 2.43d 0.44b 0.87b 2.06f 1.56a 29%/15%a [15]
Metoprolol Quinidine (250 mg BID; 3 days) CYP2D6
CYP3A4
CYP2D6
P-gp
Healthy subjects; male, white, CYP2D6 extensive metabolizers 4 3.08d 0.36b 0.70b 1.99f 2.36a 44%/15%a [15]
Metoprolol Quinidine (50 mg; single dose) CYP2D6
CYP3A4
CYP2D6
P-gp
Healthy subjects; male, white, CYP2D6 poor metabolizers 3 1.12d 0.98b 1.18b 1.30f 1.09a 35%/34%a [15]
Metoprolol Quinidine (250 mg BID; 3 days) CYP2D6
CYP3A4
CYP2D6
P-gp
Healthy subjects; male, white, CYP2D6 poor metabolizers 3 1.26d 0.88b 1.26b 1.39f 1.32a 43%/34%a [15]
Midazolam Clarithromycin (500 mg BID; 7 days) CYP3A4 CYP3A4
CYP2C19
P-gp
Healthy subjects 16 2.66 0.37 1.05a 2.79a 2.66 38%/12%a [16]
Midazolam Clarithromycin (500 mg BID; 7 days) CYP3A4 CYP3A4
CYP2C19
P-gp
Healthy subjects; elderly 16 3.2 0.35 1.16a 2.24a 4.06 44%/20%a [17]
Midazolam Erythromycin (500 mg TID; 7 days) CYP3A4 CYP3A4
P-gp
Healthy subjects 6 2.17c 0.46 1.40 3.03e 1.77 NR [18]
Midazolam Erythromycin (500 mg QID; 5 days) CYP3A4 CYP3A4
P-gp
Healthy subjects 8 1.60d 0.71b 0.93a 1.31a 1.50b 19%/13%a [19]
+ Lidocaine (1 mg/kg; 2 days) CYP3A4
CYP1A2
Midazolam Fluconazole (100 mg; single dose) CYP3A4 CYP3A4
CYP2C9
CYP2C19
Healthy subjects 12 1.3 0.78 1.01a 1.28a 1.16 10%/7% [20]
Midazolam Fluconazole (200 mg; single dose) CYP3A4 CYP3A4
CYP2C9
CYP2C19
Healthy subjects 12 1.4 0.68 1.10a 1.68a 1.20 11%/7% [20]
Midazolam Fluconazole (400 mg; single dose) CYP3A4 CYP3A4
CYP2C9
CYP2C19
Healthy subjects 12 2.0 0.54 0.93a 1.73a 1.56 17%/7% [20]
Midazolam Fluconazole (400 mg; single dose) CYP3A4 CYP3A4
CYP2C9
CYP2C19
Healthy subjects; African American CYP3A5*1/*1 6 1.62b 0.64b 0.81a 1.15a 1.35b 17%/14%a [21]
Midazolam Fluconazole (400 mg; single dose) CYP3A4 CYP3A4
CYP2C9
CYP2C19
Healthy subjects; African American CYP3A5*1/*X 7 1.67b 0.60b 0.99a 1.70a 1.43b 17%/8%a [21]
Midazolam Fluconazole (400 mg; single dose) CYP3A4 CYP3A4
CYP2C9
CYP2C19
Healthy subjects; African American CYP3A5*X/*X 6 1.97b 0.51b 0.79a 1.61a 1.44b 16%/8%a [21]
Midazolam Fluconazole (400 mg, 1 day; 200 mg QD, 5 days) CYP3A4 CYP3A4
CYP2C9
CYP2C19
Healthy subjects 12 2.02c 0.49 0.92 1.85e 1.52 1%/1%a [22]
Midazolam Itraconazole (200 mg QD; 6 days) CYP3A4 CYP3A4
CYP2J2
P-gp
Healthy subjects 12 3.22c 0.31 1.08 3.49e 2.41 16%/1%a [22]
Midazolam Ketoconazole (200 mg BID; 2 days) CYP3A4 CYP3A4
CYP2C19
P-gp
Healthy subjects; white 9 5.1 0.21 1.20a 5.97a 4.12 22%/6%a [23]
Midazolam Ketoconazole (400 mg QD; 4 days) CYP3A4 CYP3A4
CYP2C19
P-gp
Healthy subjects; female, Korean 12 4.61c 0.22 0.57b 4.61b 1.98 2%/2%b [24]
Midazolami Nelfinavir (1250 mg BID; 14 days) CYP3A4 CYP3A4 inhibition and induction Healthy subjects 16 1.83 0.57 0.79a 1.22a 1.41 2%/3%a [25]
Midazolam Rifampin [induction] (600 mg QD; 10 days) CYP3A4 CYP3A4 inhibition and induction Healthy subjects; female, Korean 12 0.48c 2.07 1.01b 0.50b 0.74 2%/2%b [24]
Midazolami Rifampin [induction] (600 mg QD; 14 days) CYP3A4 CYP3A4 inhibition and induction Healthy subjects 16 0.44 2.16 1.19a 0.54a 0.61 4%/3%a [25]
Midazolami Ritonavir (600 mg TID; 1 day; 300 mg BID; 6 days; 400 mg BID; 7 days) CYP3A4 CYP3A4 inhibition and induction Healthy subjects 16 3.31 0.29 1.04a 3.22a 2.85 21%/3%a [25]
Theophylline Cimetidine (400 mg BID; 7 days) CYP1A2
CYP3A4
CYP2E1
CYP enzymes
OCT2
MATE1
Healthy subjects; male, young 8 1.31c 0.77 1.10 1.44e 1.41 NR [26]
Theophylline Cimetidine (400 mg BID; 7 days) CYP1A2
CYP3A4
CYP2E1
CYP enzymes
OCT2
MATE1
Healthy subjects; female, young 8 1.42c 0.71 1.05 1.48e 1.43 NR [26]
Theophylline Cimetidine (400 mg BID; 7 days) CYP1A2
CYP3A4
CYP2E1
CYP enzymes
OCT2
MATE1
Healthy; male, elderly 8 1.36c 0.73 0.98 1.34e 1.31 NR [26]
Theophylline Cimetidine (400 mg BID; 7 days) CYP1A2
CYP3A4
CYP2E1
CYP enzymes
OCT2
MATE1
Healthy; female, elderly 8 1.33c 0.75 1.08 1.43e 1.36 NR [26]
Theophylline Cimetidine (1000 mg QD; 7 days) CYP1A2
CYP3A4
CYP2E1
CYP enzymes
OCT2
MATE1
Healthy subjects 7 1.56d 0.66b 1.02b 1.58f 1.84b NR [27]
Theophylline Cimetidine (1000 mg QD; 8 days) CYP1A2
CYP3A4
CYP2E1
CYP enzymes
OCT2
MATE1
Healthy subjects 9 1.33c 0.75 1.13g 1.83g 1.24 19%/5%g [28]
Theophylline Cimetidine (1000 mg QD; 8 days) CYP1A2
CYP3A4
CYP2E1
CYP enzymes
OCT2
MATE1
Patients with liver cirrhosis 9 1.22c 0.82 0.97g 1.36g 1.66 15%/9%g [28]
Theophylline Cimetidine (300 mg QID; 2.75 days) CYP1A2
CYP3A4
CYP2E1
CYP enzymes
OCT2
MATE1
Healthy subjects; male 5 1.69d 0.61 1.11h 1.90h 1.73 32%/13%h [29]
Theophylline Cimetidine (300 mg QID; 6 days) CYP1A2
CYP3A4
CYP2E1
CYP enzymes
OCT2
MATE1
Healthy subjects 10 1.46d 0.74b 1.12a 1.53a 1.38b 30%/17%a [30]
Theophylline Cimetidine (400 mg TID; 9 days) CYP1A2
CYP3A4
CYP2E1
CYP enzymes
OCT2
MATE1
Healthy subjects; male 7j 1.42 0.73 1.02a 1.30a 1.38 13%/8%a [31]
Theophylline Cimetidinek (800 mg BID; 9.5 days) CYP1A2
CYP3A4
CYP2E1
CYP enzymes
OCT2
MATE1
Patients with chronic obstructive pulmonary disease 15 1.35d 0.77b 1.10b 1.47b 1.45b 13%/6%a [32]
Theophylline Cimetidine (600 mg QID; 6 days) CYP1A2
CYP3A4
CYP2E1
CYP enzymes
OCT2
MATE1
Healthy subjects 8 1.63 0.60 1.07 2.01 1.80 NR [33]
Theophylline Ciprofloxacin (500 mg BID; 6 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2
CYP3A4
Healthy subjects 8 1.43 0.69 1.04 1.70 1.51 NR [33]
Theophylline Ciprofloxacin (500 mg BID; 7 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2
CYP3A4
Healthy subjects; male 8 1.34d 0.76b 1.02 1.36e 1.43b 21%/12%a [34]
Theophylline Ciprofloxacin (500 mg BID; 8 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2
CYP3A4
Healthy subjects; male, young 8 1.49c 0.67 1.02 1.52e 1.51 NR [26]
Theophylline Ciprofloxacin (500 mg BID; 8 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2
CYP3A4
Healthy subjects; female, young 8 1.50c 0.67 1.02 1.53e 1.48 NR [26]
Theophylline Ciprofloxacin (500 mg BID; 8 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2
CYP3A4
Healthy subjects; male, elderly 8 1.42c 0.71 1.04 1.47e 1.40 NR [26]
Theophylline Ciprofloxacin (500 mg BID; 8 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2
CYP3A4
Healthy subjects; female, elderly 8 1.40c 0.71 1.08 1.51e 1.45 NR [26]
Theophylline Ciprofloxacin (500 mg BID; 6 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2
CYP3A4
Healthy subjects 8 1.80 0.55 1.11 2.26 2.03 NR [33]
+ Cimetidine (600 mg QID; 6 days) CYP enzymes
OCT2
MATE1
Theophylline Ciprofloxacin (500 mg BID; 15 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2
CYP3A4
Healthy subjects; male, young 8 1.64c 0.61 1.08 1.78e 1.73 NR [26]
+ Cimetidine (400 mg BID; 8 days) CYP enzymes
OCT2
MATE1
Theophylline Ciprofloxacin (500 mg BID; 15 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2
CYP3A4
Healthy subjects; female, young 8 1.79c 0.56 1.02 1.84e 1.75 NR [26]
+ Cimetidine (400 mg BID; 8 days) CYP enzymes
OCT2
MATE1
Theophylline Ciprofloxacin (500 mg BID; 15 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2
CYP3A4
Healthy subjects; male, elderly 8 1.64c 0.61 1.00 1.64e 1.64 NR [26]
+ Cimetidine (400 mg BID; 8 days) CYP enzymes
OCT2
MATE1
Theophylline Ciprofloxacin (500 mg BID; 15 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2
CYP3A4
Healthy subjects; female, elderly 8 1.60c 0.63 1.08 1.72e 1.68 NR [26]
+ Cimetidine (400 mg BID; 8 days) CYP enzymes
OCT2
MATE1
Theophylline Diltiazem (120 mg TID; 6 days) CYP1A2
CYP3A4
CYP2E1
CYP3A4
CYP1A2
CYP2D6
P-gp
Healthy subjects 10 1.02c 0.98 1.11g 1.01g 1.06 9%/9%g [35]
Theophylline Enoxacin (200 mg TID; 3 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2 Healthy subjects 5 2.00c 0.50 1.09a 2.35a 2.12 33%/7%a [36]
Theophylline Famotidine (40 mg BID; 6 days) CYP1A2
CYP3A4
CYP2E1
Unknown Healthy subjects 10 0.95d 1.07b 1.12a 1.06a 1.08b 17%/16%a [30]
Theophylline Famotidinek (40 mg BID; 9.5 days) CYP1A2
CYP3A4
CYP2E1
Unknown Patients with chronic obstructive pulmonary disease 15 0.99d 1.02b 1.03b 1.02b 1.02b 6%/6%a [32]
Theophylline Nalidixic acid (500 mg QID; 7 days) CYP1A2
CYP3A4
CYP2E1
Unknown Healthy subjects; male 8 0.99d 1.04b 1.04 1.02e 1.12b NR [34]
Theophylline Norfloxacin (200 mg TID; 3 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2 Healthy subjects 5 1.08c 0.93 1.11a 1.29a 1.17 13%/7%a [36]
Theophylline Norfloxacin (400 mg BID; 7 days) CYP1A2
CYP3A4
CYP2E1
CYP1A2 Healthy subjects; male 8 1.17d 0.86b 1.02 1.19e 1.24b 18%/12%a [34]
Theophylline Ofloxacin (200 mg TID; 3 days) CYP1A2
CYP3A4
CYP2E1
Unknown Healthy subjects 5 1.00c 1.00 1.08a 1.11a 1.06 10%/7%a [36]
Theophylline Olanzapine (5 mg; 1 day; 7.5 mg; 1 day; 10 mg QD; 7 days) CYP1A2
CYP3A4
CYP2E1
Unknown Healthy subjects; male 12 0.94 1.04 1.08a 1.01a 1.02 7%/7%a [31]
Theophylline Ranitidine (150 mg BID; 7 days) CYP1A2
CYP3A4
CYP2E1
CYP3A
CYP2C9
CYP2D6
OCT2
Healthy subjects 7 1.21d 0.92b 0.97b 1.16f 1.28b NR [27]
Theophylline Verapamil (40 mg TID; 4 days) CYP1A2
CYP3A4
CYP2E1
CYP3A4
P-gp
Healthy subjects; male, white 12 1.13 0.92 0.98 1.06e 1.11 15%/11%a [37]
Theophylline Verapamil (80 mg TID; 4 days) CYP1A2
CYP3A4
CYP2E1
CYP3A4
P-gp
Healthy subjects; male, white 12 1.19 0.86 0.95 1.11e 1.11 16%/11%a [37]
Theophylline Verapamil (120 mg TID; 4 days) CYP1A2
CYP3A4
CYP2E1
CYP3A4
P-gp
Healthy subjects; male, white 12 1.28 0.82 0.90 1.10e 1.25 18%/11%a [37]
Theophylline Verapamil (120 mg TID; 8 days) CYP1A2
CYP3A4
CYP2E1
CYP3A4
P-gp
Healthy subjects 7 1.25d 0.81b 0.97b 1.21f 1.22b 45%/37%g [38]
Theophylline Verapamil (120 mg QID; 6 days) CYP1A2
CYP3A4
CYP2E1
CYP3A4
P-gp
Healthy subjects 10 1.29c 0.77 0.98 g 1.31g 1.33 6%/3%g [35]
Tolbutamide Cimetidine (1000 mg QD, 4 days; 600 mg, 1 day) CYP2C9 CYP enzymes
OCT2
MATE1
Healthy subjects 6 1.15c 0.87 1.01a 1.19a 1.13 4%/2%a [39]
Tolbutamide Cimetidine (400 mg QID; 4.5 days) CYP2C9 CYP enzymes
OCT2
MATE1
Healthy subjects 6 1.53c 0.65 0.96a 1.46a 1.46 5%/2%a [39]
Tolbutamide Primaquine (45 mg; single dose) CYP2C9 Unknown Healthy subjects 6 1.04c 0.96 0.82a 0.89a 0.90 2%/4%a [39]
Tolbutamide Sulfaphenazole (500 mg BID; 3.5 days) CYP2C9 CYP2C9 Healthy subjects 7 3.10c 0.32 0.86a 3.21a 3.07 26%/4%a [39]
  1. Pharmacokinetic values reported in the table are based on published average values, unless otherwise noted
  2. AUC area under the curve, BID twice daily, CL clearance, Con control, MATE1 Multidrug and Toxic Extrusion 1, MRT mean residence time, NAT N-acetyl transferase, NR not reported, OCT organic cation transporter, P-gp P-glycoprotein, QD once daily, QID four times a day, t1/2,z terminal half-life, Refs reference, TID three times a day, Vss volume of distribution at steady state, XO xanthine oxidase
  3. aRatios are calculated by digitization of published average plasma concentration–time profiles and performing a non-compartmental analysis
  4. bRatios are calculated for each individual using published individual pharmacokinetic data; the reported value reflects the average of each individual ratio
  5. cAUC was calculated with the equation AUC = dose/CL using known dose and reported average values of CL
  6. dAUC was calculated for each individual with the equation AUC = dose/CL using known dose and reported individual values of CL; the reported value reflects the average of each individual ratio
  7. eMRT was calculated with the equation Vss = CL·MRT using reported average values of CL and Vss
  8. fMRT was calculated for each individual with the equation Vss = CL·MRT using reported individual values of CL and Vss; the reported value reflects the average of each individual ratio
  9. gRatios are calculated by digitization of a published plasma concentration–time profile of a single representative subject, which may not be reflective of all subjects in the study
  10. hRatios are calculated by digitization of individual published plasma concentration–time profiles and performing a non-compartmental analysis; the reported value reflects the average of each individual ratio
  11. iMidazolam was dosed intravenously at the same time as an oral probe cocktail of tolbutamide, dextromethorphan, and caffeine
  12. jInteraction arm included n = 7 subjects; however, the control arm is only n = 6 as one subject dropped out of the study
  13. kA list of additional drugs being taken by these subjects with chronic obstructive pulmonary disease can be found in the original article by Bachmann et al. [32]