Editorial [Hot Topic: Modulation, Absorption and Delivery of Xenobiotics: The Synergic Role of CYP450 and P-gp Activities (Guest Editor: Nicola Antonio Colabufo)]

In designing new drugs to reach their biological target, it should be consider the synergistic role of the major systems that regulate drug permeability: P-glycoprotein (P-gp) and CYP450 metabolic enzymes. P-gp, belonging to the ABC transports family, is an efflux pump that extrudes out of the cellular barriers drugs and xenobiotics that back into the blood stream. CYP450 enzymes are a family of monooxygenases that catalyze the biotransformation of a wide variety of endogenous and exogenous compounds to give specific metabolites of the parent drug. These two mechanisms, operating in a coordinated manner, limit intracellular accumulation of xenobiotics and regulate the bioavailability, tissue distributions, and pharmacodynamic effects of drugs. Drug distribution into the Central Nervous System (CNS) is modulated by the blood-brain barrier (BBB), where, the function and expression of CYP450 enzymes and P-gp have a critical pharmacokinetic and pharmacodynamic roles. Recently, in isolated human brain microvessels, CYP1B1 and CYP2U1, have been identified as the main CYP450 isoforms present at the BBB and other studies revealed that P-gp is more present. Recent studies related to the expression, regulation and function of CYP450 enzymes and P-gp in rodent and human BBB, have been reported in the paper of Decleves X. et al. In this paper is focused also a possible interplay between some CYP450 enzymes with some ABC transporters occurring in the BBB, which makes BBB a key element determining brain concentrations of centrally acting drugs. Changes in ABC transporter expression and function are thought to be implicated in various diseases, such as cancer, epilepsy, Alzheimer's and Parkinson's diseases. The overexpression of CYP450 metabolic enzymes and P-gp at BBB level, causes drug resistance in neurological diseases such as epilepsy. In the paper of Ghosh C. et al., the role of P-gp and CYP450 enzymes in brain pathologies and the pathophysiological evolution of the drug resistant phenotype were discussed. Moreover, the experimental approaches leading to significant studies on the role of CYP450 enzymes and P-gp in the drug resistant human epileptic brain was reported. P-gp overexpression , induced by well-known chemotherapeutics agents is a major cause of multidrug resistance (MDR) of chemotherapeutic treatment in tumour cells and tissues. It is known that there is an overlap in substrate and inhibitor specificity for P-gp and CYP3A4 enzymes, so that chemotherapeutic agents also undergo metabolic transformations by various CYP450 isoforms. In the paper of Azzariti et al., data regarding the ability of some chemotherapeutics in modulating both P-gp and CYP450 enzymes are reported; in particular it is clarified whether there is a relationship between the simultaneous modulation of CYP450 and P-gp and the onset of drug resistance in tumours. A major strategy to revert MDR is the co-administration of a chemotherapeutic agent with a P-gp inhibitor. A P-gp inhibitor can concomitantly modulate CYP450 enzymes modifying pharmacokinetic properties of the administered anticancer drugs and its metabolism, causing unfavourable side effects. The paper of Darby R. et al., discusses some of the P-gp inhibitors designed and employed to date and the possible future strategies that could be implemented to achieve its design. The availability of a non-invasive imaging method which allows for measuring P-gp function or expression in vivo facilitates the identification of those patients that would benefit from treatment with P-gp modulating agents. In the article of Mairinger S. et al., the currently available P-gp radiotracers for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are described, focusing the strengths and limitations of individual probes and their potential clinical applications. This review highlights the synergistic role of P-gp and CYP450 enzymes in drug distribution, so that the simultaneously study of P-gp transport and CYP450 metabolism in drug design, for MDR and/or for neurodegenerative disorders, is fundamental. The paper of Inglese C. et al., suggests the use of everted gut sac assay, an ex vivo method that, firstly, gives simultaneous informations on absorption and metabolism; secondly, the results obtained by this assay display an high prediction degree for in vivo experiments. Mudra D. et al., describes several in vitro and in situ models to study metabolism and permeability, including transfected cell lines, isolated tissues and perfused organs. Moreover, in this paper, computational models including physiologically-based pharmacokinetic models that demonstrate the synergistic interplay between P-gp and CYP450 enzymes are reported.