Metabolism Doesn’t Just Apply to Food

The QT interval issue is only one of hundreds of disparities between men’s and women’s physiology, but it serves to illustrate just how deadly these disparities can be. In addition to this crucial area of heart functioning, women also exhibit unique attributes in the areas of bone structure and composition, body fat composition and location, tissue elasticity, and neurological function, to name a few.
Another huge difference between men and women is the way they process various compounds in their bodies. These sex-based differences mean that pharmaceuticals are digested, processed, and distributed differently in women’s systems and that women experience more unanticipated side effects from taking prescription drugs than men.
These differences were highlighted in a 2014 article by Theresa Chu, PhD, in the journal U.S. Pharmacist. She wrote, “Sex differences in metabolism (phase I and II) are believed to be the major cause of differential pharmacokinetics [responses to pharmaceuticals in the body] between men and women. Many CYP450 enzymes (phase I metabolism) show a sex-dependent difference in activity. Most of the phase II enzymes have a higher activity in men than in women.… Sex differences are also found in other pharmacokinetic parameters such as drug absorption, drug distribution, and excretion. Despite these differences between men and women, sex-specific dosing recommendations are absent for most drugs.”3 While that may seem like a lot to digest, the key takeaway is the final line.
Here’s one example of these metabolic differences at work in an unexpected place:
We’ve all heard that women metabolize alcohol differently than men. It’s recommended that women only have one alcoholic drink per day, while men can have two. And it takes only half as much alcohol to get a woman drunk as it does a man.
The reason for this is an enzyme called aldehyde dehydrogenase (ADH). Men have a lot of this enzyme—in men, ADH is present in both the stomach lining —in men, ADH is present in both the stomach lining and in the liver—and it’s very active. Women, on the other hand, have little to no ADH in the stomach lining, and it is less active in the liver. This means that men begin to metabolize alcohol immediately after they consume it and that much of it is digested before it ever gets into the bloodstream. In women, however, the alcohol must enter the bloodstream in order for the liver to secrete ADH, and so digestion is both slower and less efficient. Body fat percentage and distribution also appear to play a role; the higher a person’s body fat percentage, the higher his or her blood alcohol content after the same number of drinks.4 In general, women tend to have higher body fat percentages than men.
The result of these sex-based metabolic differences is that a man and a woman of the same height, weight, and age can consume the same amount of alcohol, but the woman will feel the effects sooner and more strongly, and after three drinks her blood alcohol level will be 25 percent higher than that of a man.
I remember learning about this many years ago in medical school; it was one of many, many facts flung at us to memorize and learn in one of our conference hall sessions. This fact stuck out to me, though. It made me wonder, Oh? Men and women are different? Why? But then, we were moving on to a different set of facts and figures, and my question receded.
Later, I saw this fact used in public health bulletins; my friends’ kids learned it in high school health classes. But there are concerns at play here beyond the public health implications of higher rates of alcohol poisoning and intoxication-related injuries in women. After all, our bodies didn’t evolve to produce ADH simply to digest booze!
As it turns out, multiple medications and compounds are broken down, at least in part, by aldehyde dehydrogenase—including the highly popular sleep aid Ambien (zolpidem).
Women metabolize Ambien differently than men for the same reasons that they metabolize alcohol differently. The breakdown of Ambien likely begins for men in the stomach; for women, in the bloodstream. (While studies have shown that ADH is at play in Ambien metabolism, there are likely many other enzymes that play a role, many of which may be sex differentiated.) The result of this difference in metabolic process is that the morning after women take the drug, their serum concentrations are nearly twice those of men—which results in grogginess, “brain fog,” and (for some) physical impairment equivalent to alcohol intoxication.
This is not acceptable. Women have busy lives, and many take sleep aids so that they can continue to function at the levels demanded of them by their many responsibilities. Because researchers didn’t understand that small differences in metabolic function between men and women can have big consequences, women were basically waking up and moving through the day impaired. In fact, some of the studies conducted around this were driving simulations; both in the lab and in real life, the driving of women on Ambien resembled that of an intoxicated person. We still don’t know exactly how many auto accident deaths and injuries have resulted from women using Ambien at the higher dose based on male physiology, but the number is not small.
Unfortunately, but also not unpredictably, this phenomenon was not discovered until many years after the drug’s release, when government monitors noticed that the vast majority of complaints regarding Ambien were filed by women or their doctors, all reporting similar side effects. This difference in rates of metabolism and serum concentrations was not considered significant in the initial drug trials (even though those trials did demonstrate that women had higher serum concentrations than men) because the researchers did not deem sex differences significant and did not differentiate adverse reactions by sex in their final findings. Male-dominated future studies (including those used to produce generic variations) did not capture this issue either.
But here’s the thing: even twenty years ago, when the drug was released, we had all the pertinent information; we knew that ADH levels in women affect the way they process certain compounds. Did drug researchers know that Ambien was broken down by ADH at the time of its release? I can’t say. But the fact is, no one put two and two together until thousands of women came forward to complain about their side effects.
Ambien is not an isolated case. In fact, a 2001 report from the Government Accountability Organization found that, out of ten prescription drugs withdrawn from the market from 1997 to 2001, eight were found to pose greater health risks for women.5 Worse, one-third of those “greater health risks” were for torsades de pointes—meaning that the drugs were withdrawn after causing sudden cardiac death in withdrawn after causing sudden cardiac death in women who were not otherwise considered at risk.

References:

  • Teresa Chu, PhD, “Gender Differences in Pharmacokinetics in Pharmacology,” U.S. Pharmacist 39, no. 9 (2014): 40–43.
  • “Absorption Rate Factors,” University of Notre Dame, https://mcwell.nd.edu/your-well-being/physical-well-being/alcohol/absorption-rate-factors.
  • “GAO-01-286R Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women,” GAO.gov, https://www.gao.gov/assets/100/90642.pdf.

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