Although we do not typically adjust the dosage of medications based on gender, there are certain medications which may have different pharmacokinetics and rates of metabolism in women versus men.

The FDA recently lowered the recommended starting dose for zolpidem in women (Ambien, Ambien CR), and strengthened the warnings about the risk of next-day driving.  The recommended initial doses are as follows:

  • Immediate-release zolpidem products (Ambien and Edluar):  5 mg for women and either 5 mg or 10 mg for men.
  • Extended-release (Ambien CR) is 6.25 mg for women and either 6.25 or 12.5 mg for men.

Pharmacokinetic studies have demonstrated that average plasma zolpidem levels are approximately 50% higher in women than in men at any given time.  This difference is independent of body weight.

This disparity in drug elimination was probably not detected at the time of the original 1992 approval for zolpidem, because prior to 1993 women were often under-represented in the pharmacokinetic assessments of new drugs.

Exactly why these gender differences exist is not well understood. A small body of literature indicates that testosterone may increase the activity of cytochrome P450 enzyme 3A4 (CYP3A4). Because zolpidem is extensively metabolized mainly by CYP3A4, testosterone enhances the metabolism of zolpidem and thus men would have lower levels of zolpidem.  If this is, in fact, the reason for this disparity, one would imagine that post-menopausal women, who have lower levels of testosterone, may be at risk for higher zolpidem levels.

What About Other Medications?

It turns out that gender affects the pharmacokinetic and pharmacodynamics profiles of many different psychotropic medications.  In a thorough review, Marazziti and colleagues review the various factors which may cause disparities in drug levels in women versus men:

Generally, women are characterized by lower levels of gastric acidity and lesser activity of some gastric enzymes, all of which are factors that increase drug plasma concentrations. Further, women have a reduced capacity for gastric elimination, lower body weight, lesser blood volume, and a greater percentage of fat mass compared to men. These factors are important in determining the absorption and distribution of drugs, and consequently their efficacy and tolerability. In particular, benzodiazepines are highly lipophilic and are accumulated in the adipose tissue with a significant increase of their half-life in women, especially when elderly.

Even the protein-binding capacity in plasma shows important sex-related differences, in the sense that women are characterized by a lower concentration of proteins compared to men, which leads, especially in the case of drugs that bind strongly to the proteins, such as TCAs and benzodiazepines, to a greater risk for more severe side effects and toxicity.

Women are characterized by both slower hepatic metabolic processes and reduced capacity for glomerular filtration compared to men. The diminished capacity of elimination of different compounds, compared to men, may expose women to a greater possibility of severe toxic effects.

As far as the enzymatic system of the cytochrome P450 is concerned, the most important sex difference involves the CYP3A4 isozyme, which is responsible for the metabolism of several psychotropic drugs. This isozyme shows a greater level of activity in young women than in men or postmenopausal women.

In many cases, the differences are subtle and probably of little clinical relevance.  In other cases, where there is a narrow therapeutic window or when there are significant side effects, these differences may be more important. There is data to support clinically meaningful differences in the levels of anti-psychotic medications and benzodiazepines; however, other drugs may be similarly affected.

Take home message: Start low, go slow, and get levels, whenever possible.

Ruta Nonacs, MD PhD

FDA Drug Safety Communication: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist)

Marazziti D, Baroni S, Picchetti M, Piccinni A, Carlini M, Vatteroni E, Falaschi V, Lombardi A, Dell’Osso L. Pharmacokinetics and pharmacodynamics of psychotropic drugs: effect of sex.  CNS Spectr. 2013 Jun;18(3):118-27.

The Drug-Dose Gender Gap (New York Times)