Cytochrome P450 inhibition by common ABC transporter inhibitors.
| Inhibitor | Transporter Inhibiteda | Transportera | P450 Inhibition (Recombinant Enzymes) | Other Transporters Inhibiteda,f | ||||
|---|---|---|---|---|---|---|---|---|
| CYP3A4 | CYP1A2 | CYP2C9 | CYP2C19 | CYP2D6 | ||||
| IC50 (μM) | ||||||||
| Cyclosporin Ab | P-gp | 1.3c | 11.7 ± 1 (P) | ND (W) | ND (W) | 51 ± 3.1 (W) | ND (W) | OATP1B1, 1B3, 2B1, NTCP, BSEP, MRP2 |
| Elacridarb | P-gp | 0.3d | 4.9 ± 1.4 (W) | 16 ± 7 (W) | 19.1 ± 3.6 (W) | 2.05 ± 0.4 (M) | ND (W) | BCRP |
| Ketoconazoleb | P-gp | 1.2c | <0.02 (P) | 30 ± 4.7 (W) | 40.6 ± 1.5 (W) | 14.6 ± 2.1 (M) | >100 (W) | |
| Nelfinavir | P-gp | 1.4c | 1.37 ± 1.2 (P) | 6.6 ± 0.9(M) | 63.1 ± 8.2 (W) | 13.2 ± 1.9 (M) | 67 ± 11 (W) | OATP1B1, BCRP |
| Quinidineb | P-gp | 2.2c | 4.5 ± 0.6 (M) | ND (W) | ND (W) | ND (W) | 0.7 ± 0.2 (P) | OCT1, OCT2, OCT3 |
| Reserpine | P-gp | 1.4c,e | 55.9 ± 4.2 (W) | ND (W) | ND (W) | <0.03 (P) | <0.2 (P) | BSEP |
| Ritonavirb | P-gp | 3.8c | 0.05 ± 0.04 (P) | ND (W) | 13.6 ± 0.8 (M) | 7.4 ± 1.5 (M) | 40.2 ± 3.5 (M) | OATP1A2, 1B1, 1B3, 2B1 |
| Saquinavir | P-gp | 6.5c | 0.5 ± 0.16 (P) | ND (W) | 27 ± 3.9 (M) | 21.3 ± 4.6 (M) | 52 ± 9 (M) | OATP1A2, 1B1, 1B3, 2B1, OCT1, OCT2 |
| Tacrolimusb | P-gp | 0.74c | 1.05 ± 0.3 (M) | ND (W) | 65 ± 1.7 (W) | 26.5 ± 1.2 (W) | ND (W) | OATP1B1 |
| Verapamilb | P-gp | 2.1c | 31.6 ± 2.4 (W) | ND (W) | 460 ± 31 (W) | 60.6 ± 8.4 (W) | ND (W) | OATP1A2, OCT1 |
| MK-571 | MRP | 10d | 11.3 ± 1.4 (M) | ND (W) | 43.1 ± 7.4 (M) | 28.5 ± 1.6 (M) | ND (W) | OATP1B1, 1B3, 2B1, P-gpd, BCRPd |
| Probenecidb | MRP | 42e | >280 (W) | ND (W) | ND (W) | 93 ± 5 (M) | ND (W) | OAT1, OAT3, OATP1B1 |
| Fumitremorgin C | BCRP | 1.3e | ND (W) | ND (W) | ND (W) | ND (W) | ND (W) | |
| Gefitinibb | BCRP | 0.4 | 39.8 ± 0.2 (W) | ND (W) | ND (W) | 36 ± 1 (W) | ND (W) | |
IC50 values are based on total concentration. Mean 6 S.E. listed, n = 3, for elacridar n = 4. The experiment was performed on three separate occasions.
> <: IC50 value predicted outside the concentration range tested; P, potent: P450 IC50 below published IC50 values for the relevant transporter; M, moderate: P450 IC50 from equal to 10-fold higher than IC50 values reported for the ABC-transporter; ND, no inhibition detected within the concentration range tested; W, weak: P450 IC50 values at least 10-fold higher than reported transporter IC50 values.
↵a Transporter data are from University of Tokyo transporter database (TP-search; Ozawa et al., 2004), and the UCSF FDA TransPortal (Morrissey et al., 2012).
↵b Recommended for in vivo as well as in vitro use (CDER, 2012).
↵c Caco-2 cell IC50 (CDER, 2006).
↵d IC50 values from MDCK cells overexpressing human transporters (Matsson et al., 2009).
↵e Ki value listed instead of IC50.
↵f Within 10-fold of main ABC transporter IC50.