Do drugs work differently in men vs women?

Although it may come as a surprise to some, women are at increased risk for adverse drug effects. More specifically, female sex is related to a 1.5- to 1.7-fold heightened risk of adverse drug reactions compared with male sex.

This biological discrepancy is largely rooted in sex-based variations in drug pharmacokinetic and pharmacodynamic parameters, as well as women often receiving higher mg/kg doses of drugs. Such differences can impact a drug’s bioavailability, efficacy, and therapeutic outcome.

Here’s an evidence-based look at sex-related differences in drug distribution, metabolism, and clearance, along with some examples.

Sex differences explained

On average, men weigh more than women. However, only a handful of drugs are dosed by weight. Women often end up receiving higher mg/kg drug doses than they should in light of specific weight differences, thus resulting in higher drug concentrations and higher drug exposure. 

Drug concentrations depend on volume of distribution and clearance. The average-weight woman has a higher percentage body fat compared with the average-weight man, and this difference impacts the volume of distribution of some drugs.

Furthermore, the renal clearance of an unchanged drug is lower in women due to lower glomerular filtration rates. After adjusting for body size and age, the glomerular filtration rate for women is 10% lower than for men. This difference in clearance is compounded by sex differences in the activity of cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes, which metabolize drugs.

“Sex differences in the activity of hepatic enzymes, drug transporters, and renal excretion will result in differences in clearance (elimination),” wrote Gail D. Anderson, PhD. “The most common families of enzymes involved in drug metabolism are the [CYP], [UGT], and N-acetyltransferase (NAT) enzymes. The primary function of the hepatic enzymes is twofold; the metabolism of endogenous compounds, like steroids and the detoxification of exogenous compounds like drugs.”

Specifically, women have decreased activities of CYP1A2, CYP2E1, and UGT; heightened activities of CYP2A6, CYP2B6, and CP3A4. 

Quantifying the issue

Of 300 new drug applications assessed by the FDA between 1995 and 2000, only 163 included sex analyses, with 20% highlighting notable sex differences in drug pharmacokinetics. In fact, 11 of these drugs demonstrated a greater than 40% difference in pharmacokinetics between men and women—yet no dosing recommendations were made based on sex!

In a 1980 prospective drug surveillance study involving 1,920 inpatients, researchers found that 83% of adverse drug reactions in men and 93% of adverse drug reactions in women were dose-related effects. Importantly, covariates—including age, number of drugs given, and length of hospital stay—did not account for this difference. 

Specific drugs to watch for

When prescribing the following drugs, it may be a good idea to keep in mind potential sex-related differences in metabolism and so forth.

Antithrombotic drugs. In a review article published in Current Medicinal Chemistry, researchers examined the correlation between sex-related differences in the use of antithrombotic therapy and clinical implications, focusing on sex-based variations in platelet biology and coagulation mechanisms.

Overall, they found that “women and men present different responses to antithrombotic drugs, reflecting gender specific variances in pharmacokinetic profile, along with the physiological characteristics of each gender.” 

“Thus, the efficacy and adverse effects of antithrombotic drugs may vary according to gender,” they concluded.

Statins. Some researchers have shown that older women who are taking statins may be at increased risk for adverse effects, particularly myalgias and diabetes, compared with men. This may be due to lower body weight, lower metabolism, and reduced muscle mass in women compared with men. The risk is highest in those women with low body weight.

Digoxin. This cardiac glycoside has positive inotropic and parasympathetic effects—properties that treat heart failure and slow conduction via the atrioventricular node, respectively.

“Digoxin has a different pharmacokinetic profile in women compared to men, displaying a reduced volume of distribution and slower renal clearance,” wrote the authors of a review article published in Cardiovascular Drugs and Therapy. “These pharmacokinetic differences may partially explain the increased mortality risk seen in women taking digoxin for heart failure.”

Calcium channel blockers. These drugs—which are indicated for a range of cardiovascular diseases, including angina, hypertension, and supraventricular tachyarrhythmias—exhibit pharmacokinetic differences in men and women. Specifically, women attain higher blood levels of amlodipine and exhibit faster oral elimination rates for verapamil. These differences may be partially attributed to lower body mass, higher activity of CYP3A4, and lower activity of P-gp in women.

Antibiotics. Various types of antibiotics that are voided unchanged in urine—including vancomycin, cefepime, and ceftazidime—exhibit decreased clearance in women. This decreased clearance is most pronounced in older women with lower body weight.

Sex-specific adverse effects

Pharmacodynamic differences in drug interactions in women increase the risk for various adverse effects, including drug-induced liver toxicity, gastrointestinal disturbances (secondary to nonsteroidal anti-inflammatory drugs), and allergic skin conditions (mostly due to antibiotics). Of elevated concern, drug-induced long-QT syndrome is also more common in women—with two-thirds of all cases occurring in women, which can open the door to lethal torsades.

On a final note, women may experience more negative drug side effects for reasons other than intrinsic differences in drug impact. For instance, women take more medications than men, on average, and are less likely to receive prescriptions that follow evidence-based guidelines. Furthermore, women are under-represented in clinical trials, which could lead to limited identification of sex-based variations in medication response, thus mitigating therapeutic potential for all women.