Expert Opinion on Drug Metabolism & Toxicology

Michael, Michael; Doherty, Margaret M

doi: 10.1517/17425255.3.6.783pmid: 18028025

Drug-metabolising enzymes (DMEs) are present in tumours and are capable of biotransforming a variety of antineoplastics. Tumoural drug metabolism is both a potential mechanism of resistance and a means of achieving optimal therapy. This review addresses the classes of DMEs, their cytotoxic substrates and distribution in specific malignancies. The limitations of preclinical and clinical studies are highlighted. Their role in predicting therapeutic response, the activation of prodrugs and the potential for their modulation for gain is also addressed. The contribution of tumoural DMEs to cancer therapy can only be ascertained through large prospective studies and supported by new technologies. Only then can efforts be concentrated in the design of better prodrugs or combination therapy to optimise individual therapy.

O'Connor, Robert; Clynes, Martin; Dowling, Paul; O'Donovan, Norma; O'Driscoll, Lorraine

doi: 10.1517/17425255.3.6.805pmid: 18028026

Treatment resistance, whether inherent or acquired, is a major problem reducing the activity of conventional and newer, molecularly targeted, cancer drugs. A more complex picture of the causes and contributions of specific forms of resistance is now emerging through application of pharmacological, proteomic and gene expression technologies and we have entered an exciting time where new molecular research tools are being applied not only to characterise the causes of such resistance, but to identify rational new treatments and treatment combinations that are being rapidly translated to clinical evaluations with increasing success. This review outlines many of the contributing causes of resistance to established cytotoxics and to the new breed of molecularly targeted agents, both monoclonal antibodies and small molecules, and the research methods being used to wage war on resistant cancer.

Behravan, Javad; Piquette-Miller, Micheline

doi: 10.1517/17425255.3.6.819pmid: 18028027

The placenta serves an important role both as a protective barrier as well as in normal fetal development. The ATP-binding cassette (ABC) proteins perform crucial functions in the distribution of nutrients and exchange of waste metabolites across the placenta. They also protect the developing fetus from xenobiotics to which the pregnant mother is exposed. Recent studies in P-glycoprotein (P-gp) deficient mdr1a and mdr1b (-/-) CF-1 mice have shown pronounced increases in fetal exposure to P-gp substrates due to increased transplacental penetration demonstrating the important protective role of P-gp to the developing fetus. The role of placental ABC transporter proteins in protecting the fetus against maternal exposure to drugs, toxins and other xenobiotics is discussed. Overall, the paucity of information available on the transplacental transfer of drugs emphasizes the need to further employ preclinical in vivo models for drug development in order to best predict fetal outcomes of drug administration to pregnant mothers.

Motika, Meike S; Zhang, Jun; Cashman, John R

doi: 10.1517/17425255.3.6.831pmid: 18028028

This review summarizes information concerning the association of the human flavin-containing monooxygenase 3 (FMO3) and human diseases. Human FMO3 oxygenates a wide variety of nucleophilic heteroatom-containing xenobiotics, including endogenous substrates and various clinically important drugs. In this article, the authors discuss the association of FMO3 with human disease, including: i) direct association of FMO3 genetic mutations to human genetic disease; ii) association of FMO3 genetic polymorphism to altered drug metabolism and, therefore, indirect association of FMO3 with drug therapeutic efficacy of human disease; and iii) the potential impact and/or effect of FMO3 transcriptional regulation during disease states. Even though many studies discussed for the latter two points are at a preliminary stage and require much more research to bring to a definite conclusion, the authors include these studies to stimulate general interest and invite further discussion.

McLean, Kirsty J; Girvan, Hazel M; Munro, Andrew W

doi: 10.1517/17425255.3.6.847pmid: 18028029

Cytochromes P450 (CYPs) are versatile oxidase catalysts that play pivotal roles in drug metabolism. They are highly regarded as biotechnological tools for their capacity to perform regio- and stereo-selective oxidations. Human CYPs source electrons for oxygen activation from one or more separate redox partner enzymes. However, several CYP enzymes are now known in which the CYP is covalently linked to a reductase system. Some of these systems offer distinct advantages over typical CYPs as efficient, self-contained units capable of important biotransformations, including synthesis of high value chemicals and pharmaceuticals. Protein engineering has been widely applied to produce variant CYP fusions with desirable activities. The review focuses on the nature and diversity of CYP/redox partner fusion enzymes and their biocatalytic potential.

De Buck, Stefan S; Mackie, Claire E

doi: 10.1517/17425255.3.6.865pmid: 18028030

In adapting to the challenge to make more informed selection of compounds for development, the pharmaceutical industry is increasingly embracing the application of mechanism-based models and prediction tools for prediction of pharmacokinetic parameters. This review first outlines the concepts and application of the major physiologically based prediction tools to extrapolate clearance, tissue distribution, and rate and extent of absorption from minimal in vitro or animal in vivo input data. Finally, the ability of these prediction tools, when placed within a generic whole body physiologically based model of pharmacokinetics, to predict plasma concentration–time profiles is briefly discussed.

Graaf, Inge AM de; Groothuis, Geny MM; Olinga, Peter

doi: 10.1517/17425255.3.6.879pmid: 18028031

Precision-cut tissue slices have been applied by many researchers because they represent an organ mini-model that closely resembles the organ from which it is prepared, with all cell types present in their original tissue-matrix configuration. Preparation and incubation methods of precision-cut tissue slices from various tissues are discussed and recommendations are given for optimal handling and culturing to retain optimal viability and functional integrity. The potential of precision-cut tissue slices from several organs to predict metabolite profiles and metabolic clearance of novel drugs, the involvement of transporters and the induction and inhibition of drug metabolism is discussed. To allow regular use of tissue slices in drug discovery and development, improvement of cryopreservation methods for precision-cut tissue slices is of great importance. It is concluded that the use of tissue slices in the pharmaceutical industry and in academic research can contribute significantly to obtain relevant information about metabolism and drug–drug interactions in various organs and pharmacokinetics of novel chemical entities in man, and thereby to the development of safe drugs.

Peterlin, B Lee; Rapoport, Alan M

doi: 10.1517/17425255.3.6.899pmid: 18028032

Migraine is a common, often disabling, neurovascular disease that has been shown to be associated with abnormal serotonergic activity. Drugs that modulate serotonin receptors are commonly used in the acute treatment of a migraine attack. Zolmitriptan, a 5-hydroxytryptophan1B/1D receptor agonist, is once such drug that is used in acute migraine therapy. Zolmitriptan is FDA approved for the treatment of acute migraine attacks and there is recent literature demonstrating its efficacy in the acute treatment of cluster attacks. It is rapidly absorbed and is detectable in the plasma within 2 – 5 min for the nasal spray formulation and within 15 min for the oral formulations. Zolmitriptan reaches peak plasma levels in 2 – 4 h and significant plasma levels are maintained for up to 6 h and lower levels for over 15 h. As zolmitriptan's metabolism is predominantly hepatic, patients with severe hepatic impairment should not receive zolmitriptan. However, only 25% of zolmitriptan is bound to plasma proteins and thus it is unlikely for drug interactions involving the displacement of highly protein-bound drugs. Zolmitriptan is generally very well tolerated and less than half of patients in clinical trials have reported adverse events, most of which are mild and transient, although rare serious cardiovascular events have been reported with all triptans. When patients are appropriately selected, zolmitriptan is both a safe and effective acute care migraine treatment. In this review the biological role of serotonin and its receptors is covered, followed by an in-depth review of the pharmacodynamics, pharmacokinetics and efficacy of zolmitriptan. Finally, the clinical application of zolmitriptan's use in patients is dicussed.

Brown, Colin A; Brown, Julia Y; Coleman, Michael D

doi: 10.1517/17425255.3.6.913pmid: 18028033

Recent developments within the National Health Service have led to an increase in personnel ‘qualified’ to prescribe a wide range of pharmacological agents. A short (38-day) Continuing Professional Development course in prescribing is deemed adequate to fully train individuals for practice. A sound understanding of prescribing medicines has important implications for patient benefit. For example, a prescriber would require some knowledge of drug absorption, distribution, metabolism and excretion, as well as aspects of drug delivery and drug–drug interactions. Drug metabolism in particular exerts a powerful influence on drug action; this can range from complete failure of efficacy through to life-threatening toxicity. Moreover, it is conservatively estimated that there may be several thousand deaths each year in the UK arising from an inadequate knowledge of drug metabolism when prescribing medicines. This one-day course focused on the importance of understanding drug metabolism on treatment strategies and outcomes, and was accessed by a range of healthcare professionals in the West Midlands area of the UK.