Table 2.
Chemical and pharmacological properties of direct-acting anticoagulants likely to be associated with drug-induced liver injury risk in humans
| Dabigatran etexilate | Rivaroxaban | Apixaban | Edoxaban | |
| Max daily dose (indication)1 | 220 (DVT prophylaxis) - 300 (NVAF) | 5 (post ACS2) - 10 (DVT prophylaxis) - 20 (NVAF) - 30 (treatment of DVT/PE) | 5 (DVT prophylaxis) - 20 (acute treatment of DVT/PE) | 60 (NVAF and DVT) |
| Bioavailability1 | 6.50% | 80%-100% | 50% | 62% |
| Protein binding | 35% | > 90% | 87% | 55% |
| Cmax (ng/mL) | 697 (at steady state after 400 mg/3 die)[54] | 450 (multiple dose 30 mg/die)[55] | 469 (single 20 mg dose)[56] | 424 (90 mg daily at day 10)[57] |
| Lipophilicity (LogP)5 | 5.17 | 1.74 | 2.22 | 1.61 |
| Biotransformation1 | Conjugation forming 4 pharmacologically active acylglucuronides | Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds | O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety | Hydrolysis (mediated by carboxylesterase 1), conjugation or oxidation by CYP3A4/5 (< 10%) |
| Hepatic metabolism1 | Only the prodrug is a substrate of P-gp; no induction/inhibition of principal isoenzymes of cytochrome P450 | CYP3A4, CYP2J2 and CYP-independent mechanisms. Substrate of P-gp and BCRP | CYP3A4/5. Substrate of P-gp and BCRP | Substrate of P-gp |
| Structural alerts associated with RM formation | NO (aniline motif)[58,59] | NO (chlorothiophene and bis-anilide motifs)[42,58] | NO (para-methoxyaniline and bis-anilide motifs)[41,58] | ND (no published data in the literature) |
| Dose-based DILI Risk Score3 | 2.68 | 1.29 | 1.29 | 1.454 |
| Cmax-based DILI Risk Score3 | 2.98 | 1.87 | 2.02 | 1.824 |
1
From official European Summary of Product Characteristics;
2
Only in EU;
3
Calculated based on formulas reported by Chen et al[34];
4
Calculated based on formulas reported by Chen et al[34] and assuming no RM formation;
5
Data obtained from Drug Bank (https://www.drugbank.ca/; source: ALOGPS). ACS: Acute coronary syndrome; BCRP: Breast cancer resistance protein; DVT: Deep vein thrombosis; NVAF: Non valvular atrial fibrillation; ND: Not determined; RM: Reactive metabolites; DITdP: Drug-induced torsade de pointes.