Table 4 Intravenous drug–drug interaction (DDI) studies with additional substrates (not 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.
Alfentanil Fluconazole (100 mg; single dose) CYP3A4 CYP3A4
CYP2C9
CYP2C19
Healthy subjects 12 1.2 0.84 0.93a 1.18a 1.18 2%/1% [20]
+ Ondansetron (4 mg; single dose) Unknown
+ Midazolam (1 mg; single dose) Unknown
Alfentanil Fluconazole (200 mg; single dose) CYP3A4 CYP3A4
CYP2C9
CYP2C19
Healthy subjects 12 1.6 0.62 0.89a 1.45a 1.36 3%/1% [20]
+ Ondansetron (4 mg; single dose) Unknown
+ Midazolam (1 mg; single dose) Unknown
Alfentanil Fluconazole (400 mg; single dose) CYP3A4 CYP3A4
CYP2C9
CYP2C19
Healthy subjects 12 2.2 0.46 0.90a 1.92a 1.73 5%/1% [20]
+ Ondansetron (4 mg; single dose) Unknown
+ Midazolam (1 mg; single dose) Unknown
Antipyrine Cimetidine (1000 mg BID; 7 days) CYP enzymes CYP enzymes
OCT2
MATE1
Healthy subjects 7 1.33d 0.76b 1.05b 1.40f 1.30b NR [27]
Antipyrine Ranitidine (150 mg BID; 7 days) CYP enzymes CYP3A
CYP2C9
CYP2D6
OCT2
Healthy subjects 7 1.08d 0.93b 1.02b 1.09f 1.06b NR [27]
Lidocaine Erythromycin (500 mg QID; 5 days) CYP3A4
CYP1A2
CYP3A4
P-gp
Healthy subjects 8 1.19d 0.96b 1.14a 1.19a 1.37b 28%/23%a [19]
+ Midazolam (0.075 mg/kg; single dose) Unknown
  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, NR, not reported, OCT organic cation transporter, P-gp P-glycoprotein, QID four times a day, Refs reference, t1/2,z terminal half-life, Vss volume of distribution at steady state
  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. 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
  6. 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