Trends in Gender Equality in the UK 1968-2011: Four Barriers to 'Equal Pay' for Women

This paper disaggregates the pay gap between men and women into four possible ‘barriers’: access to paid work; part-time versus full-time jobs; entrance into higher-paid jobs; and similar pay for equivalent work. UK data from 1968 to 2012 are analyzed, to investigate these possible barriers. All four barriers have persisted for decades, and all four ‘barriers’ tend to work in favour of men. There is evidence of progress in gender equality since 1968 – for example, the 1970 ‘Equal Pay Act’ and 1975 ‘Sex Discrimination Act’ seem to have reduced inequality; but some forms of discrimination seem immune to attempted equality legislation and change

Role of human CYP3A4 in the biotransformation of sorafenib to its major oxidized metabolites

The tyrosine kinase inhibitor drug sorafenib is used in the treatment of liver and renal cancers but adverse effects may necessitate dose interruption and under-dosage may lead to therapeutic failure. Sorafenib also undergoes cytochrome P450 (CYP)-dependent biotransformation to the N-oxide and other metabolites. However, although CYPs are major determinants of efficacy and toxicity the roles of these enzymes in the formation of multiple sorafenib metabolites are unclear. In the present study CYP-mediated pathways of sorafenib oxidation in human liver were evaluated. cDNA-expressed CYP3A4 was the major catalyst in the formation of the principal N-oxide and N-hydroxymethyl metabolites of sorafenib, as well as the minor N-desmethyl metabolite. In contrast, CYP3A5 exhibited only ∼5% of the activity of CYP3A4 and eleven other CYPs and three flavin-containing monooxygenases were inactive. In human hepatic microsomes metabolite formation was correlated with CYP3A4-mediated midazolam 1′-hydroxylation, but not with other CYP-specific substrate oxidations. In accord with these findings the CYP3A4 inhibitor ketoconazole selectively inhibited microsomal sorafenib oxidation pathways. From computational modeling studies atoms in the structure of sorafenib that undergo biotransformation were within ∼5.4 of the CYP3A4 heme. Important hydrogen bonding interactions between sorafenib and amino acids Ser-119 and Glu-374 in the active center of CYP3A4 were identified. These findings indicate that sorafenib is oxidized selectively by human CYP3A4. This information could be adapted in individualized approaches to optimize sorafenib safety and efficacy in cancer patients. © 2012 Elsevier Inc