Biologic and Molecular Mechanisms for Sex Differences in Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics: Part I

Abstract

There are pharmacological differences between women and men that have important clinical consequences. For several drugs, there is a higher incidence in women of drug-induced QT prolongation and a potentially fatal arrhythmia, torsades de pointes. This may be a reflection of the longer baseline QT interval in women. A difference in cardiovascular disease between women and men is that women have a higher mortality rate after myocardial infarction (MI). Women also have a higher rate of hemorrhagic stroke after receiving thrombolytic therapy for an MI. Differences in effectiveness of analgesics have been demonstrated, with kappa opioids providing pain relief for women but not men. Drugs may have different pharmacokinetics in women and men because of differences in phase I and phase II enzymes that metabolize drugs. Conflicting results about biological sex differences have been reported for the major drug metabolizing enzyme, cytochrome P450 3A4 (3A4) and may be related to a role for P-glycoprotein, a cell membrane transporter, reported as two times higher in male livers than those of females. It has been reported that boys need a higher dose of 6-mercaptopurine, which is metabolized by thiopurine methyltransferase (TPMT). TPMT is reported to be 14% higher in male human liver biopsies than those from females. Verapamil, a drug for angina and hypertension, has different clearance and side effects in men and women. Ethnic/racial variations have also been demonstrated with the drug metabolizing enzymes, CYP2C9, 2C19, and 2D6.

Lymphoma survival patterns by WHO subtype in the United States, 1973–2003

“…We checked the distribution of clinical features among males and females, and found that more males were diagnosed at stages III and IV (48.8% in males vs. 42.6% in females), with B-symptoms (46.7% in males vs. 39.5% in females) and died from HIV/AIDS (2.4% in males vs. 0.1% in females), which may partially explain the gender disparity. In addition, this gender disparity may also suggest different genetic, hormonal, and metabolic influences on treatment response [20][21][22], or different stress that patients bear and release [23]. Another possible explanation is that some etiological risk factors more frequently observed among males may also have a negative effect on their prognosis.…”

Coronary Intervention in 2009

“…In addition, sex differences in gastric emptying, acidity, and enzymes, in the activity of several isoenzymes in the liver, and in the glomerular filtration rate have been reported. 19 Whether the traditional risk factors are less potent in women (perhaps based on a protective effect of estrogen) or whether women have more diffuse coronary atherosclerosis to account for the observation that despite a higher prevalence of traditional risk factors in women undergoing coronary revascularization, the extent of epicardial disease detected by angiography is similar to that seen in men is unclear. However, these findings have lead to the evaluation of other potential risk factors or markers of disease in women.…”

ACCF/AHA/ACP 2009 Competence and Training Statement: A Curriculum on Prevention of Cardiovascular Disease

“…4. Pharmacologic dosing adjustment in consideration of issues of aging, 63 gender, 64 ethnicity, and comorbidities, for example, renal disease and liver disease and ethnicity. Aggressive preventive cardiovascular regimens are optimally tolerated when body weight-and renal functionadjusted, including the elderly, women, and smaller-sized men.…”