Effect of cardiopulmonary bypass on cytochrome P450 enzyme activity: implications for pharmacotherapy

For patients undergoing cardiopulmonary bypass (CPB) during cardiac surgery, there are well-documented changes in the pharmacokinetics (PK) of commonly administered drugs. Although multiple factors potentially underpin these changes, there has been scant research attention on the impact of CPB to alter the activities of cytochrome P450 (CYP) isoenzymes. PK changes during cardiac surgery with CPB have the potential to adversely affect the safety and efficacy of pharmacotherapy and increase the risk of drug–drug interactions. Clinically significant changes in drug PK during CPB are likely to be prominent for drugs where CYP metabolism is a major clearance (CL) mechanism. However, clinical data from patients undergoing CPB surgery in support of this hypothesis are lacking, leaving a significant knowledge gap. In this review, we address the effects of CPB on the release of pro-inflammatory cytokines, in surgeries with and without CPB, both pre and post initiation of surgery. We reviewed literature to explore the relationship between the release of pro-inflammatory cytokines, and the expression and activities of CYP enzymes. Through this approach, we provide new insight on the effects of CPB on the PK of drugs administered to patients in the clinical setting. Future research to address this knowledge gap will have considerable impact to assist clinicians with optimizing pharmacotherapy in this patient population.     

State-of-the-art Tools for Computational Site of Metabolism Predictions: Comparative Analysis,Mechanistical Insights,and Future Applications

In drug design, it is crucial to have reliable information on how a chemical entity behaves in the presence of metabolizing enzymes. This requires substantial experimental efforts. Consequently, being able to predict the likely site/s of metabolism in any compound, synthesized or virtual, would be highly beneficial and time efficient.

In this work, six different methodologies for predictions of the site of metabolism (SOM) have been compared and validated using structurally diverse data sets of drug-like molecules with well-established metabolic pattern in CYP3A4, CYP2C9, or both. Three of the methods predict the SOM based on the ligand's chemical structure, two additional methods use structural information of the enzymes, and the sixth method combines structure and ligand similarity and reactivity. The SOM is correctly predicted in 50 to 90% of the cases, depending on method and enzyme, which is an encouraging rate. We also discuss the underlying mechanisms of cytochrome P450 metabolism in the light of the results from this comparison.     

Antidepressant Drugs in the Elderly — Rôle of the Cytochrome P450 2D6

Depression, the most common mental health problem of the elderly, is often under-diagnosed and under-treated. As patients age, antidepressant pharmacological treatment becomes more complicated due to an increased risk of adverse drug events. These risks are associated with age-related physiological changes and individual variability in drug metabolism related to several factors, the most frequent of which is polymedication as a result of coexisting chronic illnesses.

Comedications induce drug interactions that depend on the patient's metabolic capacity, linked to the genetically determined cytochrome P450 enzyme (CYP450) function. The effect of some isoenzyme polymorphisms on the pharmacokinetics of many antidepressants and other psychotropic drugs is well characterized.

The author approaches successively the notions of the cytochrome P450 (2D6), its role in drug biotransformation, and the importance of knowing its substrates, inhibitors and inducers in order to predict drug interactions. The clinical significance of this notion, and the help that could be given by genotyping, and phenotyping are also explained. The author's experience on the relationship between drug side effects and patient metabolic status, and on the antidepressant interactions with fluoxetine, fluvoxamine and citalopram, is given in order to rationalize and individualize antidepressant choice in elderly.     

Hepatoprotective and antioxidant potential of Asphodeline lutea (L.) Rchb. roots extract in experimental models in vitro/in vivo

The aim of this study was to investigate the effect of Asphodeline lutea (L.) Rchb. dry root extract (ALE) administered alone and against carbon tetrachloride (CCl₄)-induced liver injury in vitro/in vivo. The dried roots of A. lutea were extracted with 70% ethanol and was characterized with HPLC-UV. Hepatoprotective potential was investigated by in vivo/in vitro assays in Wistar rats as well as antioxidant properties. At concentrations ranging from 10 to 200 μg/mL of ALE significant cytotoxic effects on isolated hepatocytes were found. ALE showed some toxicity in Wistar rats discerned by increased ALT (Alanine transaminase), ALP (Alkaline phosphatase) activities and MDA (malondialdehyde) quantity, decreased GSH (reduced glutathione) levels without affecting the activity of the antioxidant enzymes (GPx (Gluthatione peroxidase), GR (Glutathione reductase) and GST (Glutathione-S-transferase activity)). The antioxidant and hepatoprotective potential of ALE was also observed in vitro/in vivo against CCl₄-induced liver injury, where ALE normalizes all the examined parameters perturbated by CCl₄ administration. In addition, ALE preserved the decreased cytochrome P450 level and EMND (Ethylmorphine-N-Demethylase) activity without affecting AH (Aniline 4-Hydroxylase) activity. ALE is rich in anthraquinones, naphthalenes and caffeic acid. The pro-oxidant effects of ALE could be due to naphthalene and anthraquinone bioactivation pathways involving toxic metabolites.     

CYP2F1 genetic polymorphism: Identification of interethnic variations

Since human cytochrome P450 2F1 (CYP2F1) is predominantly expressed in lung tissue and is involved in the metabolism of various pneumotoxicants with potential carcinogenic effects, variations in the nucleotidic sequence of its gene may contribute to interindividual and interethnic differences in the susceptibility to lung tumorigenesis. The aim of the current study was to compare the frequency of a previously reported frameshift mutation, namely c.14_15insC, responsible for the synthesis of a severely truncated protein, between several populations of different ethnic origins. The frequencies of this polymorphism were 26.1, 51.6, 42.7 and 22.9% in French, Gabonese, Senegalese, and Tunisian population samples, respectively, thereby representing a substantial inter ethnic variation in the CYP2F1 gene. These findings provide data for further studies that investigate the potential association of CYP2F1 haplotypes with an incidence of lung cancer genesis in respect of ethnicity.