TABLE 4

Summary of data inputs and outputs for δAUC predictions for a set of P450-mediated DDIs

Dose size/interval and observed δAUC were retrieved from the listed references. Human pharmacokinetics parameters (CL, F, t1/2, ka, and oral Fabs) were sourced from several key compendiums including Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th and 10th eds (Hardman et al. 1996); Dollery's Therapeutic Drugs, 2nd ed (1999); Taeschner and Vozeh's Drug Data Handbook, 3rd ed (1998), and Bertz and Granneman (1997).

In Vivo Substrate

Inhibitor

Dose

t

CL/F

t1/2

ka

Fabs

[I]in

fup

b/pa

[I]in,u

Predicted δAUC using Iin,u/Ki

Simulated δAUC using Simcyp v7.1

Observed δAUC

References
mg h ml/min h /min μM μM Median (5th-95th percentile)
Metoprolol Amitriptyline 75 24 1677 21 0.020b 0.9 3.6 0.01 1.0 0.03 1.0 1.0 (1.0-1.0) 1.4 Kirch et al., 1984
Propranolol Chlorpromazine 50 8 1881 30 0.020b 1 2.4 0.02 1.48 0.04 1.2 1.2 (1.1-1.3) 1.7 Vestal et al., 1979
Metoprolol Cimetidine 250 6 692 2 0.011 0.9 16.5 0.90 14.83 1.3 1.1 (1.0-1.1) 1.6 Kirch et al., 1982
Propranolol 250 19.8 1.0 17.80 1.4 1.4 (1.2-1.6) 1.9 Kirch et al., 1982
Propranolol 300 16.5 14.83 1.5 1.4 (1.2-1.7) 1.5 Donn et al., 1984
Metoprolol Diltiazem 30 8 2173 4 0.028 0.9 1.1 0.41 1.0 0.43 1.0 1.1 (1.0-1.3) 1.3 Tateishi et al., 1989
Propranolol 30 3.2 1.30 1.0 1.0 (1.0-1.1) 1.5 Tateishi et al., 1989
Propranolol 90 1.1 0.43 1.1 1.1 (1.0-1.2) 1.3 Hunt et al., 1990
Metoprolol Diphenhydramine 75 12 711 5 0.020b 0.8 5.4 0.36 1.0 2.38 1.7 1.2 (1.1-1.3) 1.6 Hamelin et al., 2000
Desipramine Fluoxetine 20 24 1120 47 0.009 1 0.5 0.06 0.55 0.05 1.2 2.1 (1.3-3.6)c 4.8 Preskorn et al., 1994
Desipramine 60 1.4 0.15 1.5 2.1 (1.4-3.6)c 7.4d Bergstrom et al., 1992
Imipramine 60 1.4 0.15 1.5 3.8 (2.0-7.7)c 3.3d Bergstrom et al., 1992
Tolterodine 20 0.5 0.05 1.1 N.D. 4.8 Brynne et al., 1999
Desipramine Fluvoxamine 100 24 1498 15 0.008 1 2.0 0.28 0.55 1.03 1.2 1.4 (1.3-1.7) 1.1 Spina et al., 1993
Imipramine 100 2.0 1.03 1.7 2.1 (1.7-2.8) 3.6 Spina et al., 1993
Imipramine Labetalol 200 24 7350 4 0.020b 1 9.0 0.38 1.0 3.38 1.6 1.4 (1.1-1.8) 1.5 Hermann et al., 1992
Metoprolol Mexiletine 75 12 531 10 0.020b 1 7.6 0.58 1.0 4.42 1.3 1.1 (1.1-1.2) 1.8 Sakamoto et al., 1995
Metoprolol Omeprazole 40 24 991 1 0.1 0.7 7.1 0.03 0.60 0.24 1.0 1.0 (1.0-1.0) 1.0 Andersson et al., 1991
Propranolol 20 3.6 0.20 1.0 1.0 (1.0-1.0) 1.0 Henry et al., 1987
Propranolol Propafenone 225 8 2380 4 0.020b 1 10.5 0.16 0.61 2.73 5.5 2.6 (1.6-4.6) 2.1 Kowey et al., 1989
Desipramine Quinidine 200 24 463 11 0.014 0.9 7.4 0.23 0.92 1.81 29 19 (11-34) 7.5 Brosen and Gram, 1989
Imipramine 200 7.4 1.81 2.3 4.8 (1.8-10) 1.5 Brosen and Gram, 1989
Metoprolol 100 3.7 0.90 9.1 3.5 (1.9-6.5) 3.2 Johnson and Burlew, 1996
Desipramine Ritonavir 250 12 147 4 0.014 0.8 11.8 0.02 0.55 0.32 1.4 1.2 (1.1-1.5) 2.5 von Moltke et al., 1998
Desipramine Sertraline 50 24 2660 23 0.007 1 0.9 0.01 1.0 0.01 1.0 1.0 (1.0-1.0) 1.3 Preskorn et al., 1994;
Desipramine 100 1.8 0.02 1.0 1.0 (1.0-1.0) 1.5 Alderman et al., 1997
Desipramine 150 2.6 0.03 1.0 1.0 (1.0-1.0) 1.5 Kurtz et al., 1997
Imipramine 150 2.6 0.03 1.0 1.0 (1.0-1.1) 1.7 Kurtz et al., 1997
Metoprolol Verapamil 120 8 4773 4 0.020 1 4.0 0.12 0.77 0.60 1.1 1.1 (1.1-1.5) 1.3 Keech et al., 1986
Propranolol

120

4.0

0.60
1.0
1.0 (1.0-1.0)
1.4
McCourty et al., 1988; Murdoch et al., 1991
• N.D., not determined.

• a Blood/plasma ratios of inhibitors were sourced as follows: amitriptyline (Rollins et al., 1980), chlorpromazine (Shibata et al., 2000), diltiazem (Naritomi et al., 2003), fluoxetine, fluvoxamine, omeprazole, ritonavir (SimCYP Simulator v7.1), propafenone (Trenk et al., 1989), and quinidine and verapamil (Shibata et al., 2002). For those compounds where b/p ratio has not been obtained a value of 1 has been used. All the IC50,u values of the inhibitors are reported in Table 1, and Ki,u values were determined as described under Materials and Methods. Where an IC50,u value of > 100 μM is reported, a nominal Ki,u value of 50 μM was used. [I]in,u and Ki,u values for the inhibitors together with the estimates of fmCYP for desipramine, imipramine, tolterodine, propranolol, and metoprolol (Table 3) were used in eq. 1 to generate predicted δAUC values.

• b Where ka could not be retrieved from the literature the mean value of 0.02/min was used. [I]in was calculated using equation 2. [I]in,u values = [I]in × fup determined in this laboratory.

• c Using active uptake factor into hepatocytes of 1000 for fluoxetine.

• d Steady state of inhibitor not reached.