Structure-Based Methods for the Prediction of the Dominant P450 Enzyme in Human Drug Biotransformation: Consideration of CYP3A4, CYP2C9, CYP2D6

Abstract

Metabolic drug-drug interactions are receiving more and more attention from the in silico community. Early prediction of such interactions would not only improve drug safety but also contribute to make drug design more predictable and rational. The aim of this study was to build a simple and interpretable model for the determination of the P450 enzyme predominantly responsible for a drug's metabolism. The P450 enzymes taken into consideration were CYP3A4, CYP2D6 and CYP2C9. Physico-chemical descriptors and structural descriptors for 96 currently marketed drugs were submitted to statistical analysis using the formal inference-based recursive modelling (FIRM) method, a form of recursive partitioning. Generally accepted knowledge on metabolism by these enzymes was also used to construct a hierarchical decision tree. Robust methods of variable selection using recursive partitioning were utilised. The descriptive ability of the resulting hierarchical model is very satisfactory, with 94% of the compounds correctly classified.

Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment

“…In leave-one-out crossvalidation, 89% of all compounds in the training set were correctly classified. The achieved predictivity for an external data set of 233 compounds was equal 83%, a substantial improvement compared with the value achieved by Manga et al (2005). Promising results were also obtained for the decision tree based model, which used three descriptors only and gave the values of 88% in LOO-CV and about 80% for the external data set.…”

“…EFSA reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors. (2006) 1008 compounds Percentage human plasma protein binding Turner et al (2004b) 62 drugs Human plasma protein binding; total and renal clearance 320 drugs Percentage PPB, urinary excretion and other ADME data Kalgutkar et al (2005) (464 references) Metabolic pathways Structural alerts Manga et al (2005) 147 drugs CYP metabolism CYP isoforms predominantly responsible for their metabolism (CYP3A4/2D6/2C9) Yap et al (2006) 503 compounds Clearance (CL tot ) Total clearance in humans…”

“…The authors used a dataset originally compiled by Manga et al (2005), containing drugs which are predominately metabolised by CYP3A4, CYP2D6 or CYP2C9. The dataset to build and internally validate the model consisted of 146 (96+50) compounds (80 CYP3A4 substrates, 45 CYP2D6 substrates and 21 CYP2C9 substrates).…”

Selecting Relevant Descriptors for Classification by Bayesian Estimates: A Comparison with Decision Trees and Support Vector Machines Approaches for Disparate Data Sets

“…[22,23] Additional data were taken from ref. [24][25][26][27] We removed those compounds from our set that could not be identified unambiguously, or that were not consistently assigned as substrate, respectively nonsubstrates. This gave rise to about 670 compounds for each of the three isoforms CYP3A4, CYP2D6, and CYP2C9, whereby for the latter ones a strongly disparate relation of substrates to nonsubstrates is apparent (see Figure 5).…”

Untitled

“…In many cases inhibition of CYP leads to undesired growth of the administered therapeutic agent. These are the powerful oxidizing agents in living systems, therefore many drugs can be oxidized by more than one P450 enzyme 2 . CYP450 enzymes play an important role in endobiotic and xenobiotic metabolic processing 3 .…”