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In vitro‐in vivo extrapolation of CYP2D6 inactivation by paroxetine: prediction of nonstationary pharmacokinetics and drug interaction magnitude
Author(s) -
Venkatakrishnan K.,
Obach R.,
Bertelsen K.,
Moltke L. L.,
Greenblatt D. J.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.144
Subject(s) - chemistry , pharmacology , cyp2d6 , pharmacokinetics , in vivo , drug interaction , desipramine , enzyme , medicine , biochemistry , cytochrome p450 , biology , antidepressant , microbiology and biotechnology , hippocampus
Attempts at predicting drug‐drug interactions (DDI) perpetrated by paroxetine (PX) from in vitro data have utilized reversible enzyme inhibition models and have been unsuccessful to date, grossly underpredicting interaction magnitude. Recent data from our laboratories have provided evidence for mechanism‐based inactivation (MBI) of CYP2D6 by PX (Bertelsen et al., 2003). We have predicted the pharmacokinetic consequences of CYP2D6 inactivation by PX from in vitro inactivation kinetics (k inact 0.17 min −1 , unbound K I 0.35 μM) and estimated enzyme‐available inhibitor concentrations, using a mathematical model of MBI (Mayhew et al., 2000). The model‐predicted accumulation ratio of PX at 30 mg QD was 5 times that expected from single dose kinetics, which is in excellent agreement with the observed 5‐6‐fold greater ratio. The magnitude of DDI produced by 20‐30 mg/day PX with desipramine, risperidone, perphenazine, atomoxetine, (S)‐metoprolol and (R)‐metoprolol have been predicted, considering the contribution of CYP2D6 to their oral clearance. Predicted interaction magnitudes (fold‐increase in AUC) were 5, 5, 4, 6, 4 and 6‐fold, respectively, and are in reasonable agreement with observed values of 5, 6, 7, 7, 5 and 8–fold, respectively. Failure to consider microsomal binding in vitro adversely affected the model's predictive accuracy. The sensitivities of these predictions to accuracy in estimating inhibitor concentrations and CYP2D6 half‐life have been characterized. Clinical Pharmacology & Therapeutics (2004) 75 , P38–P38; doi: 10.1016/j.clpt.2003.11.144