Current Drug Metabolism - Volume 8, Issue 5, 2007

The topic of mechanism-based inactivation (MBI) of cytochrome P450 enzymes has been recently emerging as one of ever increasing importance. While our knowledge of some of the biochemistry and chemistry of the phenomenon of MBI of P450 enzymes has been with us for over three decades, the ramifications of MBI in drug discovery and clinical pharmacokinetics have been appreciated only more recently. While drug Read More

Cytochrome P450 constitute a superfamily of heme-containing enzymes that catalyze the oxidative biotransformation of structurally diverse xenobiotics including drugs. Inhibition of P450 enzymes is by far the most common mechanism which can lead to DDIs. P450 inhibition can be categorized as reversible (competitive or non-competitive) or irreversible (mechanism-based inactivation). Mechanism-based P450 inact Read More

This commentary discusses the approaches to, and key considerations in the in vitro-in vivo extrapolation of drug-drug interactions (DDI) resulting from mechanism-based inactivation (MBI) of cytochrome P450 (CYP) enzymes and clinical pharmacologic implications. In vitro kinetic assessment and prediction of DDI produced via reversible inhibition and MBI rely on operationally and conceptually distinct approaches. DDI risk ass Read More

In this article approaches to predict human pharmacokinetics (PK) are discussed and the capability of the exemplified methodologies to estimate individual PK parameters and therapeutic dose for a set of marketed oral drugs has been assessed. For a set of 63 drugs where the minimum efficacious concentration (MEC) and human PK were known, the clinical dose was shown to be well predicted or in some cases over-esti Read More

We have analyzed several members of drug-metabolizing enzymes (DMEs) and other polymorphisms in genes implicated in tumor aggressivity regarding possible links between specific genetic variability in systemic drug bioavailability and toxicity in breast cancer patients treated with adjuvant anthracycline-based treatment. PCR-RFLP and sequencing analyses technique were used for evaluating fourteen previously ide Read More

Trimethylaminuria (fish odor syndrome) is a metabolic disorder characterized by the inability to convert malodorous dietaryderived trimethylamine (TMA) to odorless TMA N-oxide by the flavin-containing monooxygenase 3 (FMO3). Mutations of the FMO3 gene were investigated in Japanese trimethylaminuria that showed low FMO3 metabolic capacity. Novel polymorphisms in the FMO3 gene causing stop codons at Cys197, Tr Read More

The aim of the present study was to develop and improve methods for phenotyping of CYP2E1, an important enzyme in the biotransformation of many industrial chemicals, therapeutic drugs and endogenous substances. The possibility to measure CYP2E1 activity in lymphocytes by using p-nitrophenol as a substrate and CYP2E1 protein levels by flow cytometry were studied in vitro. Further, the conventional chlorzoxazone m Read More

Polyphenolic compounds are abundant in the human diet and gram quantities are ingested daily. The consumption of polyphenols is expected to rise due to the use of dietary supplements and public health initiatives promoting the consumption of more fruits and vegetables. It is known that these dietary polyphenols are extensively metabolized. Many of these compounds are therefore are expected to compete with other su Read More

To date, the majority of therapeutic peptides and proteins have to be administered via parenteral routes, which are painful and inconvenient. Consequently, “injectable-to-oral-conversions” are highly on demand. Apart from a poor membrane uptake, however, an extensive presystemic metabolism of orally given peptide drugs is responsible for a comparatively very poor oral bioavailability. This presystemic metabolism in Read More

Calcium ion is an essential structural component of the skeleton. There is growing evidence for the importance of nutrition in the maintenance of bones and joints health. Nutritional imbalance combined with endocrine abnormalities may be involved in osteoporosis. For example, essential fatty acids and their metabolites were reported to have beneficial action in osteoporosis. The mechanism by which fatty acids prevent osteop Read More