Editor's Note: This is the fifth article in a series on sex-based differences in the biology of males and females. The final article in the series will cover sex-based differences in life expectancy.

Lisa Damiani
More than 30 years ago, researchers noted for the first time the pharmacokinetic differences between men and women. They found that women pass antipyrine, a drug used to study liver metabolism, more quickly than men; this occurred around ovulation and during the luteal phase of their menstrual cycles. But, says Mary J. Berg, professor of pharmacy, University of Iowa, this initial difference was "just a scientific notation;" the researchers didn't set out to look for dissimilarities.

Since then, just a few common drugs have been studied exclusively for sex differences. "We still have a long way to go," says Berg. "There aren't that many studies done on drugs in the market." In fact, it was only in 1999 that the National Institutes of Health held a scientific meeting on the subject. Investigation in this area is not merely academic; the issue of different metabolism rates has proven deadly for some women.

One reason these studies have not been done, according to Michael Smolensky, professor of environmental physiology, University of Texas School of Public Health at Houston, is funding is hard to come by. Also, the studies are complicated and require many subjects in many categories to conduct them properly. Susan Wood, the Food and Drug Administration's director of the Office of Women's Health, counters that the issue was, and still is, a question of clinical relevance. The historic assumption, she explains, was that variability in the population in both men and women would mask any sex-based differences. It has only been in the past decade, as more knowledge was accumulated about women's health, that sex-based differences were deemed important questions to ask. Courtesy of the University of Iowa

Mary J. Berg
While hormones do play a part in explaining some sex-based differences in drug metabolism, other confounding factors such as diet, body weight, cigarette and alcohol consumption, other medications, time of day, and age also play a role. In general, premenopausal women metabolize many types of drugs faster than men such as the asthma drug theophylline, the antibiotic erythromycin, the anti-inflammatory methyl prednisolone, and anticonvulsants used to treat epilepsy such as phenytoin derivatives. By contrast, women seem to be slower at metabolizing select antidepressants. Raymond Woosley, vice president of the Arizona Health Sciences Center in Tucson, notes that some researchers believe that drugs which block the iKr potassium channel are more potent in women than in men.

Case in Point

One of the more far-reaching instances of sex-based differences in responses to drugs is a life-threatening condition called torsades de pointes, a cardiac arrhythmia that has a greater risk of developing in women. This problem only started to draw attention when a small percentage of young women who were taking the antihistamine Seldane died unexpectedly. The drug was then taken off the market.

Drugs that cause this disorder lengthen the distance between depolarization and repolarization activity in the heart, called the QT interval (the time period needed for the heart to recharge between beats). "We should have known that [Seldane] was causing harm to women because we've known for decades that women have a longer QT interval than men," says Woosley, who has extensively studied drug effects on QT. (See www.torsades.org or www.qtdrugs.org for a list of all drugs that can cause these arrhythmias.) "It's not really a difference in drug metabolism but a difference in responsiveness," he explains. "Women's hearts are in fact twice as sensitive."

Researchers think that sex hormones cause the difference in the interval length. The QT interval is the same in children until puberty, at which time it shortens in boys. It's also known that sex hormones, which are obviously changing by the time puberty hits, affect the activity of the cells' potassium channels, which in turn govern the interval.

Nearly 40 drugs in use can lengthen the QT interval in some patients, a handful of which have been taken off the market. (See www.fda.gov/medwatch/safety.htm) "It's a common problem in every drug class that's on the market today and in every drug class being developed," says Woosley.

Breaking it Down

Investigators who study the liver are trying to understand basic mechanisms in an effort to explain sex-based differences. Bernard Shapiro, professor of biochemistry, University of Pennsylvania School of Veterinary Medicine, uses rats to study how liver enzymes called cytochrome P450s (or CYPs) metabolize drugs differently. Shapiro's work found that male and female rats express P450 isoforms differently; he is currently looking at this relationship in cultured human hepatocytes. Humans probably have 40 to 50 different isoforms, with each person expressing differing amounts, combinations of which metabolize each drug. In general, women and men may express a different suite of P450s or many of the same ones at different levels.

Growth hormone determines which P450s are expressed, and Shapiro's group found that male and female rats secrete different profiles of growth hormone over a 24-hour period. Females secrete more pulses over the circadian cycle which the P450s detect, but males and females still secrete the same amount over 24 hours. Females secrete more pulses that are smaller and in a continuous pattern, while males secrete larger pulses that are interrupted by periods devoid of growth hormone.

It's not the hormone's presence or absence, but its pulse profile, to which cells respond. Shapiro says there is good, but not yet conclusive, evidence that this scenario is also true in humans. And it is this contrasting suite of liver enzymes between males and females that may explain why some drugs are broken down differently between the sexes. Leslie Benet, professor of biopharmaceutical sciences, University of California, San Francisco, studies drug substrates for the liver and gut enzyme, cytochrome P450 3A and the transporter, P-glycoprotein. These proteins work together to metabolize drugs. More than half of human drugs, such as cancer-fighting drugs, immune suppressants, protease inhibitors, and cardiovascular disease medications, are broken down by cytochrome P450 3A. Transporters shunt drugs out of certain cells where they are not needed.

The current thinking among pharmaceutical re-searchers, says Benet, is that the transporter is responsible for the sex-based differences in metabolism; the transporter ultimately controls access to the liver and gut enzymes. His group surmises that this action is related to fluctuating progestins and estrogens during a woman's menstrual cycle. In ongoing studies, they have found that P-glycoproteins present in vaginal and endometrial tissue, and perhaps other tissues, oscillate with a woman's menstrual cycle. Their levels are high in the mid-luteal phase and low in the follicular phase. It is because of oscillations like these that Smolensky stresses the importance of including chronopharmacological studies on circadian as well as menstrual cycles in pharmacokinetics and pharma-codynamics, to better understand differences in a drug's efficacy and metabolism.

An example of varied metabolism is the response of female epileptics to phenytoin. This anticonvulsant is used to treat seizures, but because it is cleared faster in the days prior to the onset of menses, seizures are more likely to occur at that time. Thus, some women take carbamazepine instead.
Courtesy of William Jusko, University of Buffalo William Jusko

The reason behind the differences could also be the drugs themselves. In 1993, William J. Jusko, professor of pharmaceutical sciences, State University of New York, Buffalo, found that women metabolize the corticosteroid methylprednisolone more quickly than men and that women were more sensitive to the steroid's effects as measured by the cortisol concentrations and the lymphocyte count in their blood. Then, last year, his group found that prednisolone did not show a marked difference in the metabolism rate between men and women. The two compounds are similar in structure except for the addition of a methyl group, which most likely accounts for the difference in activity.

What's Ahead

Last summer, the General Accounting Office reported that the FDA was not effectively monitoring drug data for analysis of sex differences in safety and efficacy. In general, the FDA has no quarrel with the GAO's report. According to Wood, mechanisms were in place prior to the report to improve analysis by sex, such as developing a demographics worksheet and standardized reviewer templates. The agency has outlined a way to look for differences during the development of medicines (Gender studies in product development: Scientific issues and approaches. Executive Summary, U.S. FDA, 1999, www.fda.gov/womens/executive.html). "We don't want to alarm people; there's no smoking gun," says Wood. "But there is enough evidence to raise questions and to push for more research."

The FDA is moving toward developing a database that will ultimately track the demographics of clinical trials by sex, race/ethnicity and age, among other variables. Karen Young Kreeger (kykreeger@aol.com) is a contributing editor.