Present perspectives on the automated classification of the G-protein coupled receptors (GPCRs) at the protein sequence level

The G-protein coupled receptors--or GPCRs--comprise simultaneously one of the largest and one of the most multi-functional protein families known to modern-day molecular bioscience. From a drug discovery and pharmaceutical industry perspective, the GPCRs constitute one of the most commercially and economically important groups of proteins known. The GPCRs undertake numerous vital metabolic functions and interact with a hugely diverse range of small and large ligands. Many different methodologies have been developed to efficiently and accurately classify the GPCRs. These range from motif-based techniques to machine learning as well as a variety of alignment-free techniques based on the physiochemical properties of sequences. We review here the available methodologies for the classification of GPCRs. Part of this work focuses on how we have tried to build the intrinsically hierarchical nature of sequence relations, implicit within the family, into an adaptive approach to classification. Importantly, we also allude to some of the key innate problems in developing an effective approach to classifying the GPCRs: the lack of sequence similarity between the six classes that comprise the GPCR family and the low sequence similarity to other family members evinced by many newly revealed members of the family.

Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

The small intestine poses a major barrier to the efficient absorption of orally administered therapeutics. Intestinal epithelial cells are an extremely important site for extrahepatic clearance, primarily due to prominent P-glycoprotein-mediated active efflux and the presence of cytochrome P450s. We describe a physiologically based pharmacokinetic model which incorporates geometric variations, pH alterations and descriptions of the abundance and distribution of cytochrome 3A and P-glycoprotein along the length of the small intestine. Simulations using preclinical in vitro data for model drugs were performed to establish the influence of P-glycoprotein efflux, cytochrome 3A metabolism and passive permeability on drug available for absorption within the enterocytes. The fraction of drug escaping the enterocyte (F(G)) for 10 cytochrome 3A substrates with a range of intrinsic metabolic clearances were simulated. Following incorporation of P-glycoprotein in vitro efflux ratios all predicted F(G) values were within 20% of observed in vivo F(G). The presence of P-glycoprotein increased the level of cytochrome 3A drug metabolism by up to 12-fold in the distal intestine. F(G) was highly sensitive to changes in intrinsic metabolic clearance but less sensitive to changes in intestinal drug permeability. The model will be valuable for quantifying aspects of intestinal drug absorption and distribution.

Estimating the scope for savings in referrals and drug prescription costs in the general Practice units of a UK primary care trust

This paper explores the potential for cost savings in the general Practice units of a Primary Care Trust (PCT) in the UK. We have used Data Envelopment Analysis (DEA) to identify benchmark Practices, which offer the lowest aggregate referral and drugs costs controlling for the number, age, gender, and deprivation level of the patients registered with each Practice. For the remaining, non-benchmark Practices, estimates of the potential for savings on referral and drug costs were obtained. Such savings could be delivered through a combination of the following actions: (i) reducing the levels of referrals and prescriptions without affecting their mix (£15.74 m savings were identified, representing 6.4% of total expenditure); (ii) switching between inpatient and outpatient referrals and/or drug treatment to exploit differences in their unit costs (£10.61 m savings were identified, representing 4.3% of total expenditure); (iii) seeking a different profile of referral and drug unit costs (£11.81 m savings were identified, representing 4.8% of total expenditure). © 2012 Elsevier B.V. All rights reserved.

Drug-induced bilateral transient myopia with the sulphonamide sulphasalazine

Whereas there are numerous reported ocular side effects from systemic sulpha medication, most are rare and reversible, with myopia being the most common reaction observed. A case report is presented of sudden bilateral onset of -1.0 DS of myopia (from -3.0 to -4.0 DS) in a young adult female following the addition of a sulphonamide (sulphasalazine) to oral non-steroidal anti-inflammatory treatment (meloxicam) for rheumatoid arthritis. The myopia regressed to -3.50 DS after 2 weeks when all medication was withdrawn and stabilised at this level when subsequent treatment was resumed after 8 weeks with the non-steroidal anti-inflammatory drug celecoxib. The case indicates that account needs to be taken of the possibility that relatively modest myopic shifts encountered in young adult contact lens wearers may be associated with concomitant systemic medication. © 2003 The College of Optometrists.

Physiologically based pharmacokinetic modelling in drug delivery

The application of pharmacokinetic modelling within the drug development field essentially allows one to develop a quantitative description of the temporal behaviour of a compound of interest at a tissue/organ level, by identifying and defining relationships between a dose of a drug and dependent variables. In order to understand and characterise the pharmacokinetics of a drug, it is often helpful to employ pharmacokinetic modelling using empirical or mechanistic approaches. Pharmacokinetic models can be developed within mathematical and statistical commercial software such as MATLAB using traditional mathematical and computation coding, or by using the Simbiology Toolbox available within MATLAB for a graphical user interface approach to developing pharmacokinetic (PBPK) models. For formulations dosed orally, a prerequisite for clinical activity is the entry of the drug into the systemic circulation.