title: Quantitative Prediction of Drug Interactions Caused by CYP1A2 Inhibitors and Inducers.
abstract: A simple method to predict drug-drug interactions mediated by cytochrome P450 enzymes (CYPs) on the basis of in vivo data has been previously applied for several CYP isoforms but not for CYP1A2. The objective of this study was to extend this method to drug interactions caused by CYP1A2 inhibitors and inducers.
  
  
  
  First, initial estimates of the model parameters were obtained using data from the literature. Then, an external validation of these initial estimates was performed by comparing model-based predicted area under the concentration-time curve (AUC) ratios with observations not used in the initial estimation. Third, refined estimates of the model parameters were obtained by Bayesian orthogonal regression using Winbugs software, and predicted AUC ratios were compared with all available observations. Finally, predicted AUC ratios for all possible substrates-inhibitors and substrates-inducers were computed.
  
  
  
  A total of 100 AUC ratios were retrieved from the literature. Model parameters were estimated for 19 CYP1A2 substrate drugs, 26 inhibitors and seven inducers, including tobacco smoking. In the external validation, the mean prediction error of the AUC ratios was -0.22, while the mean absolute error was 0.97 (37 %). After the Bayesian estimation step, the mean prediction error was 0.11, while the mean absolute error was 0.43 (22 %). The AUC ratios for 625 possible interactions were computed.
  
  
  
  This analysis provides insights into the interaction profiles of drugs poorly studied so far and can help to identify and manage significant interactions in clinical practice. Those results are now available to the community via a web tool ( http://www.ddi-predictor.org ).
authors.affiliation: Service Pharmaceutique, Hôpital Gériatrique Pierre Garraud, Hospices Civils de Lyon, 136 rue du Commandant Charcot, 69322, Lyon Cedex 05, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Gabriel
authors.affiliation: ISPB-Faculté de Pharmacie de Lyon, Université de Lyon, Université Lyon 1, Lyon, France.|Service Pharmaceutique, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Tod
authors.affiliation: Service Pharmaceutique, Hôpital Gériatrique Pierre Garraud, Hospices Civils de Lyon, 136 rue du Commandant Charcot, 69322, Lyon Cedex 05, France. sylvain.goutelle@chu-lyon.fr.|ISPB-Faculté de Pharmacie de Lyon, Université de Lyon, Université Lyon 1, Lyon, France. sylvain.goutelle@chu-lyon.fr.|UMR CNRS 5558, Laboratoire de Biométrie et Biologie Evolutive, Université Lyon 1, Villeurbanne, France. sylvain.goutelle@chu-lyon.fr.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Goutelle
mesh_terms: D019540:Area Under Curve; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D008954:Models, Biological; D012907:Smoking
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D003577:Cytochrome P-450 Enzyme System; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A