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Sex Differences in the Pharmacologic Effects of Antiretroviral Drugs: Potential Roles of Drug Transporters and Phase 1 and 2 Metabolizing Enzymes
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International AIDS Society-USA Topics in HIV Medicine June/July 2005
Ighovwerha Ofotokun, MD, MSc
Dept of Internal Medicine, Div of Infectious Diseases, Emory University School of Medicine
"These observed lower expressions of Pgp in women suggest that women might be more likely than men to achieve higher cellular and tissue concentrations of antiretroviral drugs that are Pgp substrates. This may partially explain the increased frequency and severity of adverse reactions and perhaps the enhanced efficacy of some of these drugs in women compared with men."
Sex differences in the pharmacologic effects of antiretroviral drugs are increasingly being reported. Emerging evidence suggests that women may be at increased risk of developing adverse effects of antiretroviral drugs. Several mechanisms have been proposed to explain sex differences in drug effects, including physiologic differences between men and women and the influence of sex hormones on drug metabolism. This article reviews sex-related variations in the levels of expression and activities of drug transporters and metabolizing enzymes involved in the disposition of the antiretroviral drugs, and postulates that these variations may partly explain sex differences in the responses to these drugs. Studies that explore relationships between levels of expression and activities of relevant enzymes and drug transporters and observed sex-related differences in treatment responses to antiretroviral drugs will help clarify the extent to which molecules involved in drug disposition affect sex differences in treatment response.
Knowledge is growing about sex differences in regulating the expression and activity of phase 1 and phase 2 drug-metabolizing enzymes, which are probably related to endogenous sex hormones. 47 Activities of CYP1A2 and CYP2E1 may be higher in men than in women,48-51 whereas CYP2D6 activity may be higher in women than in men.52 Sex differences in CYP2C19 activity appear to show ethnic variations: CYP2C19 activity is higher in Chinese, Jewish-Israeli, and African American women than in men of these ethnic backgrounds.53-55 No sex difference in the activity of CYP3A seems to exist.56 Although hepatic clearance of drugs that are substrates for both CYP3A and Pgp (such as erythromycin and verapamil) appears to be higher in women than in men, this may be explained largely by lower hepatic Pgp activity in women.57-59
The activities of some phase 2 isoen-zymes also exhibit sex differences. Thiopurine methyltransferase (TPMT) activities are 14% lower in liver tissues from women than from men.60 Similarly, levels of catechol-O-methyltransferase activity are lower in women.61 The activity of several isoenzymes of the uridine 5-diphosphate glucuronosyltransferase (UGT) superfamily, including UGT1A1, UGT1A6, UGT1A8, UGT1A9, and UGT1A10, is also lower in women.62-65 A study from Finland shows that phenol sulfotransferase activity is more than 60% lower in women than men.65 Sex differences in regulation of the activities of the cellular kinases that activate nRTIs remain undefined.
Based on available studies, enzymes involved in phase 1 reactions may have only a limited role, if any, in the sex-related differences in pharmacologic effects of the antiretroviral drugs. The activity of CYP3A, the principal isoform of the CYP450 system, in the biotransformation of PIs and NNRTIs does not appear to be influenced by sex. Although CYP2D6 activity is reported to be higher in women than in men, the role of this isoform in the metabolism of ritonavir and delavirdine is limited. In contrast, activities of many isoenzymes involved in phase 2 reactions are lower in women than in men, suggesting that antiretroviral agents (or their metabolites) that undergo biotransformation by these pathways may reach higher concentrations in the cells and tissues of female HIV patients than in male patients.
Sex differences in the activities of cellular kinases that activate nRTIs remain unclear. Studies to explore sex differences in the expression and activities of these key enzymes in the metabolism of the nRTIs will be of interest for 2 reasons. First, there are documented sex differences between men and women in the development of adverse effects associated with the nRTIs, in particular, lactic acidosis. Second, both the efficacy and the toxic effects of the nRTIs are related to the phosphorylated products of the cellular kinases.
The drug transporter P-glycoprotein (Pgp) is an important component of the xenobiotic cascade that influences the bioavailability of drugs. Because of the key role played by Pgp in drug disposition, sex-mediated differences in its expression and activities could result in differences between men and women in the pharmacologic activities of drugs transported by this molecule. Recent observations indicate that Pgp influences the disposition of antiretroviral drugs, particularly HIV PIs.One example of such evidence was provided by Schuetz and colleagues,24 who evaluated the expression of Pgp by hepatic cells in 41 subjects and found that Pgp activity among women was only one third to one half that of men. In another study, involving 36 men and 25 women with B-cell chronic lymphocytic leukemia, Steiner and colleagues25 showed that women were almost 2 times less likely than men to be positive for the MDR1 genotype that encodes for Pgp expression. Sex differences in Pgp expression have also been demonstrated in rats26 and Chinese hamsters.27 Sex-dependent expression has been described for other transporters, including sodium taurocholate cotransporting polypeptide (NTCP)28 and the organic cation transporter 2 (OCT2).29 These observed lower expressions of Pgp in women suggest that women might be more likely than men to achieve higher cellular and tissue concentrations of antiretroviral drugs that are Pgp substrates. This may partially explain the increased frequency and severity of adverse reactions and perhaps the enhanced efficacy of some of these drugs in women compared with men.
Conclusion
HIV infection has become a chronic, treatable illness, especially in the developed countries, as many HIV-infected patients are on antiretroviral therapy and are living longer. The adverse effects of these drugs, particularly in women, are a growing source of concern, because many observational studies have shown that women experience greater toxic effects with all classes of antiretroviral drugs. Although sex differences in the effects of these drugs may be due in part to physiologic and hormonal differences between men and women, variations in the activities of drug transporters and metabolizing enzymes involved in phase 1 and 2 reactions may also be involved. Further studies are needed to relate activities of these enzymes and drug transporters and observed sex differences to the effects of the antiretroviral drugs. Such studies will enhance our ability to develop new agents that are better tolerated by both sexes, and to identify drug dosages that are most effective for women
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