P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms

Abstract

In this study, IC 50 shift and time-dependent inhibition (TDI) experiments were carried out to measure the ability of amiodarone (AMIO), and its circulating human metabolites, to reversibly and irreversibly inhibit CYP1A2, CYP2C9, CYP2D6, and CYP3A4 activities in human liver microsomes. The [I] u /K i,u values were calculated and used to predict in vivo AMIO drug-drug interactions (DDIs) for pharmaceuticals metabolized by these four enzymes. Based on these values, the minor metabolite N,N-didesethylamiodarone (DDEA) is predicted to be the major cause of DDIs with xenobiotics primarily metabolized by CYP1A2, CYP2C9, or CYP3A4, while AMIO and its N-monodesethylamiodarone (MDEA) derivative are the most likely cause of interactions involving inhibition of CYP2D6 metabolism. AMIO drug interactions predicted from the reversible inhibition of the four P450 activities were found to be in good agreement with the magnitude of reported clinical DDIs with lidocaine, warfarin, metoprolol, and simvastatin. The TDI experiments showed DDEA to be a potent inactivator of CYP1A2 (K I = 0.46 mM, k inact = 0.030 minute 21 ), while MDEA was a moderate inactivator of both CYP2D6 (K I = 2.7 mM, k inact = 0.018 minute 21) and CYP3A4 (K I = 2.6 mM, k inact = 0.016 minute 21). For DDEA and MDEA, mechanism-based inactivation appears to occur through formation of a metabolic intermediate complex.Additional metabolic studies strongly suggest that CYP3A4 is the primary microsomal enzyme involved in the metabolism of AMIO to both MDEA and DDEA. In summary, these studies demonstrate both the diversity of inhibitory mechanisms with AMIO and the need to consider metabolites as the culprit in inhibitory P450-based DDIs.

Application of Static Modeling ­­in the Prediction of In Vivo Drug–Drug Interactions between Rivaroxaban and Antiarrhythmic Agents Based on In Vitro Inhibition Studies

“…Taken together, our results indeed underscore the potential contributions of NDEA and NDBA as inhibitory metabolites. NDEA (k inact /K I = 387 min 21 /mM 21 ) being a more potent time-dependent inactivator of CYP3A4 compared with amiodarone (k inact /K I = 130 min 21 / mM 21 ) was consistent with previous in vitro studies using midazolam as a probe substrate (McDonald et al, 2015). Likewise, NDEA (K i = 5.36 mM) being more potent than amiodarone (K i = 8.94 mM) in the inhibition of P-gp-mediated rivaroxaban transport was also well aligned with previous transport assays using digoxin as a probe substrate (Katoh et al, 2001).…”

“…The common structural features in these antiarrhythmic agents and their metabolites are the alkylamine and furan that are in turn associated with mechanismbased inactivation (MBI) of P450 (Orr et al, 2012). Indeed, corroborating previous findings, our laboratory established the reversible and irreversible inhibition of CYP3A4-and CYP2J2-mediated metabolism of FDA-recommended probe substrates by amiodarone and NDEA (Ohyama et al, 2000;McDonald et al, 2015;Karkhanis et al, 2016) as well as dronedarone and NDBD (Hong et al, 2016;Karkhanis et al, 2016). Independently, amiodarone and dronedarone have been reported as P-gp inhibitors (FDA, 2009b(FDA, , 2012.…”

Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations

“…Methanolic extracts were prepared from three commercially available kratom products (coded K-50, K-51, and K-52) as described (Flores-Bocanegra et al, 2020;Todd et al, in revision). The extracts and mitragynine were tested as inhibitors of CYP2C9, CYP2D6, and CYP3A activities using a cocktail approach (McDonald et al, 2015;McDonald et al, 2020) with modifications. In brief, a kratom extract (2, 10, 20 µg/mL) or mitragynine (1, 10, 100 µM) was incubated at 37°C in 96-well plates with HLMs or HIMs (0.05 mg/mL) and the probe substrates diclofenac (CYP2C9, 4 µM), dextromethorphan (CYP2D6, 4 µM), and midazolam (CYP3A, 2 µM) in potassium phosphate buffer (0.1 M, pH 7.4); the final organic (methanol) concentration (v/v) and incubation volume was <0.8% and 400 µL, respectively.…”

Rosuvastatin‐Induced Rhabdomyolysis – Possible Role of Ticagrelor and Patients’ Pharmacogenetic Profile

“…Rosuvastatin and amiodarone were immediately excluded from the therapy assuming that rhabdomyolysis was caused by this drug interaction as amiodarone has the potential to interact with many drugs . The hallmark biomarker for muscle injury is CK level in serum; it rises within 12 hr of muscle injury, but has its peak value at 24–72 hr with a serum half‐life of approximately 1.5 days.…”