Relevant in vivo concentrations of amiodarone, dronedarone, and their metabolites that were incorporated into mechanistic static models
| Parameter | Amiodarone | NDEA | Dronedarone | NDBD |
|---|---|---|---|---|
| μM | ||||
| [I]H (inactivation)a | 0.12 | 0.18 | 0.00063 | 0.0045 |
| [I]H (reversible inhibition)b | 0.15 | 0.18e | 0.021 | 0.0045e |
| [I]Gc | 7.50 | NA | 40.4 | NA |
| [I]d | 2.99 | 2.80 | 0.21 | 0.21 |
Drug-dependent parameters necessary for the derivations of these in vivo concentrations are presented in Supplemental Table 2. NA, not applicable.
↵a [I]H (inactivation) is the concentration of inactivator at the enzyme active site in the liver defined as the systemic steady-state unbound peak plasma concentration (fu,b × Css,max).
↵b [I]H (reversible inhibition) is the concentration of inhibitor at the enzyme active site in the liver defined as the hepatic portal inlet steady-state unbound Cmax [fu,b × (D × ka × Fa/QH) + Css,max], where D is total daily oral dose of the inhibitor, ka is the oral absorption rate constant, Fa is the product of the fractions absorbed and escaping intestinal metabolism, and QH is the hepatic blood flow (1450 ml/min).
↵c [I]G is the concentration of inactivator/inhibitor at the enterocyte during absorption defined as D × ka × fa/QH, where fa is the fraction of the inactivator/inhibitor dose absorbed into the gut wall and Qg is the enterocytic blood flow (248 ml/min).
↵d [I] is the peak plasma concentration of the inhibitor.
↵e [I]H (reversible inhibition) for NDEA and NDBD is defined as the systemic steady-state unbound peak plasma concentration.