Table 3.

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

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]

Pharmacokinetic values reported in the table are based on published average values, unless otherwise noted

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, t_1/2,z terminal half-life, Refs reference, TID three times a day, V_ss volume of distribution at steady state, XO xanthine oxidase

^aRatios are calculated by digitization of published average plasma concentration–time profiles and performing a non-compartmental analysis

^bRatios are calculated for each individual using published individual pharmacokinetic data; the reported value reflects the average of each individual ratio

^cAUC was calculated with the equation AUC = dose/CL using known dose and reported average values of CL

^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

^eMRT was calculated with the equation V_ss = CL·MRT using reported average values of CL and V_ss

^fMRT was calculated for each individual with the equation V_ss = CL·MRT using reported individual values of CL and V_ss; the reported value reflects the average of each individual ratio

^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

^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

ⁱMidazolam was dosed intravenously at the same time as an oral probe cocktail of tolbutamide, dextromethorphan, and caffeine

^jInteraction arm included n = 7 subjects; however, the control arm is only n = 6 as one subject dropped out of the study

^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]