The magnitude of the decrease in substrate drug exposure by P-gp induction is generally less than that of CYP3A. Most P-gp inducers increased total bioavailability with minor impact on renal clearance. |
Rifampin is the most potent P-gp inducer resulting in average reduction of substrate exposure ranging between 20 and 67%. For other inducers, the reduction in P-gp substrate exposure ranged from 12 to 42%. |
A lower reduction in exposure of the P-gp substrate was observed with a lower dose of the inducer and/or if the administration of the inducer and substrate was simultaneous, i.e., not staggered. |
1 Introduction
1.1 P-Glycoprotein (P-gp) Expression and its Role in Major Excretory Organs
1.2 Challenges with Characterizing Transporter-Mediated Drug–Drug Interactions
1.3 Effect of P-gp Inducers on P-gp Substrates
2 Literature Search
3 Key Findings
3.1 Mechanism of P-gp Induction
3.2 P-gp Substrates
P-gp substrate | Absorption | Distribution | Elimination | Half-life | PK linearity | BDDCS classification | References |
---|---|---|---|---|---|---|---|
Digoxin | Tmax = 1–3 h F = 60–80% | Vd ~ 6 L/kg fu ~ 70% | 50–70% renal excretion | 1.5–2 days | Linear | 3 | |
Fexofenadine | Tmax = 2.6 h F = approximately 33% | Vd = 5.4–5.8 L/kg fu = 30–40% | 5% metabolized, 11% renal excretion, 80% in feces (could be unabsorbed or biliary excretion) | 14.4 h | Linear up to a total daily dose of 240 mg | 3 | |
Dabigatran etexilate | F = 3–7% Tmax = 1 h | Vd = 0.625–0.875 L/kg fu = 65% | Esterase-catalyzed hydrolysis to dabigatran (active) | 12–17 h | Linear 10–400 mg | 1 | [59] |
Talinolol | Tmax = 3.2 h F = 55% | Vd = 3.3 ± 0.5 L/kg fu = 45% | 57% renal clearance and 43% non-renal clearance (could be biliary elimination); metabolic clearance is only minimal (< 1%) | 11.9 h | Dose-dependent absorption (non-linear) | 3 |
3.2.1 Digoxin
3.2.2 Fexofenadine
3.2.3 Dabigatran Etexilate
3.3 P-gp Inducers
P-gp inducer | Dosing regimen used in DDI studies with P-gp substrate | Staggered dosing relative to P-gp substrate | Half-life (h) | Tmax (h) | Mechanism of induction | References |
---|---|---|---|---|---|---|
Rifampin | 600 mg qd or 300 mg bid for 6–16 days | Yes | 2.5 | 2 | Strong PXR agonist | |
Phenytoin | 0.2 g for 15 days | No | 23–69a | 3–12a | Strong CAR agonist, weak PXR agonist | |
Carbamazepine | Total daily doses of 300–600 mg. Doses were administered as 600 mg qd, 300 mg bid, or 100 mg tid | 35 | 2–3 | Strong CAR agonist, weak PXR agonist | ||
St. John’s wort extract | 300 mg tid standardized to contain 3% hyperforin | 4.5b | 17b | Strong PXR agonist | ||
Rifabutin | 300 mg qd for 20 days | Yes | 45 | 2.5–3 | PXR agonist | |
Quercetin | 500 mg daily to 1.5 g daily (500 mg tid) for 7–13 days | 3.5 | 3 | PXR and CAR agonist | ||
Curcumin | 600 mg daily (200 mg tid) or 1 g qd for 6–14 days | 0.5c | NAc | PXR agonist |
P-gp inducer | P-gp inducer dose/dosing regimen | P-gp substrate | P-gp substrate dose (alone or after multiple P-gp inducer doses) | Staggered dosing of P-gp inducer and substrate | ∆ AUC (%) | ∆ Cmax (%) | ∆ t½ (%) | References |
---|---|---|---|---|---|---|---|---|
Rifampin | 600 mg qd for 9 days | Talinolol | Multiple 100 mg talinolol qd doses PO | Yes | − 35.2 | − 37.8 | − 15 | [63] |
30 mg talinolol doses, IV infusion over 30 min | − 21 | − 19 | − 11 | |||||
600 mg qd for 16 days | Digoxin | Single 1 mg doses PO under fasted conditions | − 30.1 | − 58 | − 4 | [64] | ||
Single 1 mg doses, IV infusion over 30 min | − 20 | Unchanged | − 10 | |||||
300 mg bid for 14 days | Single 0.25 mg doses PO | − 25 | − 38 | − 10 | [65] | |||
600 mg qd for 6 days | Fexofenadine | Single 60 mg doses PO | − 46.5 | − 32.5 | − 7 | [66] | ||
600 mg qd for 7 days | Dabigatran | Single 150 mg doses PO | − 67 | − 65.5 | NR | [67] | ||
2 mg qd for 10 days | Dabigatran | Single 75 mg doses PO (cassette dosing) | + 19 | + 7 | NR (minimal difference based on concentration vs. time profile) | [68] | ||
10 mg qd for 10 days | − 40.6 | − 43.2 | ||||||
75 mg qd for 10 days | − 62 | − 61.6 | ||||||
600 mg qd for 10 days | − 66.6 | − 69.5 | ||||||
Phenytoin | 0.2 g bid for 15 days | Digoxin | 1 mg initial dose of digoxin IV on day 1, then β-acetyldigoxin 0.4 mg qd to steady-state | No (administered concomitantly) | − 22 | NR | − 30 | [69] |
Carbamazepine | 100 mg tid (for a total daily dose of 300 mg) for 7 days | Fexofenadine | Single 60 mg doses PO | No (administered concomitantly) | − 39 | − 35 | − 12 | [74] |
200 mg qd for 2 days, followed by 400 mg qd for 14 days | Digoxin | Multiple 0.13 mg doses PO | Yes | Fold change not reported although specified as ‘absent effect’ | [98] | |||
Initiated at 100 mg bid and escalated to final 300 mg bid dose over 1 week | Dabigatran | Single 75 mg doses PO (cassette dosing) | Yes | − 28.6 | − 33.4 | NR | [75] | |
600 mg qd for 18 days | Talinolol | Multiple talinolol 100 mg qd doses | Yes | − 12.8 | NR | + 3.3 | [76] | |
St. John’s wort | St. John’s wort for 14 days (300 mg tid, standardized to contain 3% hyperforin) | Digoxin | Single 0.25 mg doses PO | No (administered concomitantly) | − 23 | − 36 | − 8 | [65] |
High-dose hyperforin-rich extract (LI 160) | Multiple doses (individualized digoxin dosing based on Ctrough levels administered alone for the initial 7 days, followed by 14 days of co-medication with St John’s wort or placebo) PO | − 24.8 | − 37 | NA | [83] | |||
4 g hypericum powder with similar hyperforin content as LI 160 (1 g qid) | − 26.6 | − 38 | NA | |||||
2 g hypericum powder with half the hyperforin content of LI 160 (0.5 g qid) | − 17.7 | − 21 | NA | |||||
St. John’s wort for 12 days (300 mg tid, standardized to contain 3% hyperforin) | Talinolol | Single 50 mg doses PO | No | − 31 | − 21 | − 19 | [101] | |
Single 30 mg doses IV | No | − 7 | NA | − 14 | ||||
St. John’s wort for 13 days (days 3–15; 300 mg tid, standardized to contain 3% hyperforin) | Fexofenadine | Single 180 mg dose PO | Yes | − 46 | − 39 | + 10 | [82] | |
Quercetin | 500 mg qd for 13 days | Talinolol | Single 100 mg dose PO | Yes | − 20 | − 24 | − 8 | [86] |
500 mg tid for 7 days | Fexofenadine | Single 60 mg dose PO | No (administered concomitantly) | + 55 | + 68 | + 4 | [87] | |
Curcumin | 200 mg tid for 6 days | Talinolol | Single 50 mg dose PO | No (administered concomitantly) | − 42 | − 29 | + 9 | [91] |
1000 mg qd for 14 days | Talinolol | Single 100 mg dose PO | Yes | + 81 | + 29 | + 13 | [90] | |
Rifabutin | 300 mg qd for 20 days | Dabigatran | Single 75 mg dose PO (cassette dosing) | Yes | − 19.1 | − 13.3 | NR | [75] |
Genistein | 1000 mg genistein or placebo qd for 14 consecutive days | Talinolol | Single 100 mg dose PO | Yes | − 12 | − 10 | − 29 | [112] |