Gender-Specific Drug Effects

In a recent Pharmacy Times article, I described a number of gender-specific diseases and noted that there are also a number of cases where a drug can have different effects on male and female patients.¹ A significant part of the reason may be that men and women metabolize drugs differently. Sex-specific patterns of drug metabolism are due to the different ways males and females secrete growth hormone. The pattern in males, established by testosterone, consists of bursts of growth hormone alternating with periods of low hormone production. Females, by contrast, produce growth hormone at a constant rate.² Women also have a more active CYP 3A4 system than men. (CYPs are a superfamily of isozymes that modulate the oxidative metabolism of drugs in the liver.)

This last difference is particularly important because this group of enzymes is responsible for the metabolism of up to 60% of all drugs. Drugs metabolized by the CYP 3A4 system are extensively cleared by females, whereas drugs cleared by other isozymes are usually cleared faster by males.³ The sex-specific difference in CYP 3A4 activity is related to estrogen and progesterone, which regulate the activity of CYP 3A4 at the gene level.

Male - female differences in body fatness may account for the increased volumes of distribution for lipophilic drugs (eg, benzodiazepines) in females. This difference may result in higher unbound concentrations of such drugs in women.⁴ Males also have higher levels of creatinine in serum and urine and higher rates of creatinine clearance than females. That difference is related to the greater lean body mass of males.

From the above information, it would appear that the disparity in drug metabolism would be considered in research. This disparity is not always taken into account, however, and there are a number of examples where sex differences have not been routinely considered.

• In a large longitudinal study of the effects of a cholesterol-lowering drug, the drug was administered to 3806 men and no women⁵
• The Multiple Risk Factor Intervention Trial examined mortality in 12,866 men only⁶
• A review published in the Journal of the American Medical Association surveyed the literature from 1960 to 1991 on clinical trials of medications used to treat acute myocardial infarction; women were included in only about 20% of these studies⁷

Drugs from classes as diverse as antihistamines (terfenadine), antibiotics (erythromycin), and antiarrhythmic drugs (d,l sotalol) can induce torsades de pointes, a potentially lethal cardiac rhythm. The risk of having this complication is far greater in females than in males. It is likely to be related to sex differences in cardiac ion channel function, which induce a greater prolongation of the QTc interval in females.⁸ Other sex differences in side effects also have been noted. For example, females are twice as likely as males to develop a cough while taking angiotensin-converting enzyme inhibitors.⁹

Psychotropic drugs are more commonly prescribed to female patients, and young women are more sensitive to their effects. This disparity holds true even when the doses are corrected for body size. Women show a more pronounced response and are more likely to suffer unpleasant or unwanted side effects. The responses may be due to the effect of estrogen on the brain or to differences in the pharmacokinetics of the drugs.

On the other hand, tricyclic antidepressants are more effective in treating panic attacks in male patients. There is a difference in the way male brain cells bind to serotonin. Men?s serotonin receptors on platelets have fewer binding sites for serotonin than do those of women.²

Recently it was found that the effects of digoxin are gender-specific. This discovery was made after reviewing results from a large randomized study of 5281 men and 1519 women with congestive heart failure who were treated with either digoxin or placebo. The data were analyzed separately for men and women. The authors found that women, and not men, had a higher all-cause mortality when taking digoxin than when taking placebo.¹⁰

Many of today?s prescribed drugs marketed prior to the mid 1990s were tested almost exclusively on men. One reason was that many women feared that an untested medication might affect their ability to bear children. If women were included, they were generally postmenopausal and not subject to cyclic variations in hormone levels. In 1993, the FDA established specific guidelines for evaluating gender differences in how drugs were to be tested. The package inserts for new drugs now list differences in pharmacokinetics, including pediatric, geriatric, and gender- specific differences. This section of a package insert should be consulted carefully. Oftentimes there will be major differences in peak plasma concentration and other parameters, and gender-related dosage adjustment may be required.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. D. Ryan, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: dryan@mwc.com.