Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women

Abstract

Pharmacological response depends on multiple factors and one of them is sex-gender. Data on the specific effects of sex-gender on pharmacokinetics, as well as the safety and efficacy of numerous medications, are beginning to emerge. Nevertheless, the recruitment of women for clinical research is inadequate, especially during the first phases. In general, pharmacokinetic differences between males and females are more numerous and consistent than disparities in pharmacodynamics. However, sex-gender pharmacodynamic differences are now increasingly being identified at the molecular level. It is now even becoming apparent that sex-gender influences pharmacogenomics and pharmacogenetics. Sex-related differences have been reported for several parameters, and it is consistently shown that women have a worse safety profile, with drug adverse reactions being more frequent and severe in women than in men. Overall, the pharmacological status of women is less well studied than that of men and deserves much more attention. The design of clinical and preclinical studies should have a sex-gender-based approach with the aim of tailoring therapies to an individual's needs and concerns. LINKED ARTICLESThis article is part of a themed section on Biological Sex and Cardiovascular Pharmacology. To view the other articles in this section visit http://dx.doi.org/10. 1111/bph.2014.171.issue-3 Abbreviations ACEI, inhibitor of angiotensin converting enzyme; ADE, adverse drug effect; ARB, antagonist of angiotensin receptor 1; CV, cardiovascular; CYP, cytochrome P450 enzymes; ET-1, endothelin-1; HMG-CoA, hydroxymethylglutaryl coenzyme A; OC, oral contraceptives; RAS, renin angiotensin system; SGD, sex-gender difference IntroductionOptimal pharmacological therapy depends on many factors. Some of these factors are biological (metabolism, genetic and epigenetic backgrounds, age and sex) (Becquemont et al., 2006), while others depend on the environment such as care provider-patient relationship. In view of the numerous biological (sex) and psychosocial-cultural (gender) differences, women and men can be considered as two different categories (Legato, 2009). However, sex-gender difference (SGD) only started to acquire the right relevance in the latter part of the last century, although Hippocrates, describing the symptoms of gout, had written 'A woman does not take the gout unless her menses has stopped ' (Enomoto and Endou, 2005), indicating a SGD in susceptibility rather than the development of a disease. The first pharmacological SGD was described in 1932 (Nicholas and Barron, 1932), when it was demonstrated that the hypnotic effect of hexobarbital lasted longer in female than in male rats. Later, it was shown that this difference is dependent on the metabolic process (Quinn et al., 1958). Nowadays, SGDs in pharmacokinetic parameters are well known and have been recently and extensively (Gandhi et al., 2004;Anderson, 2005;Franconi et al., 2007; 2011a,b;Soldin and Mattison, 2009). The SGDs in pharmacodynamics are not so well-known, but the...

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“…Literature has shown that females are more prone to develop adverse effects than males 27 . There is 1.5 to 1.7 folds increased risk of developing adverse drug reactions in women than men 28 .…”