In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.

The past 20 years have seen substantial work on the modeling of ductile damage and fracture. Several factors explain this interest. (i) There is a growing demand to provide tools which allow to increase the efficiency of structures (reduce weight, increase service temperature or load, etc.) while keeping or increasing safety. This goal is indeed first achieved by using better materials but also by improving design tools. Better tools have been provided which consist (ii) of material constitutive equations integrating a physically-based description of damage processes and (iii) of better numerical tools which allow to use the improved constitutive equations in structural computations which become more and more realistic. This article reviews the material constitutive equations and computational tools, which have been recently developed to simulate ductile rupture.