By Bella Rudoy
The lack of female representation in clinical studies has become increasingly overlooked in recent years. Studies found that 80% of the studies done in 2010 consisted of male bias. As of 2016, 70% of biomedical experiments did not report sex as a variable of interest. Eighty-six medications approved by the FDA were found to have a gender gap in a study conducted at the University of California. These staggering numbers are only a snapshot of the many clinical drug trials being conducted without regard to sex differences. Studies show that, overall, women experience more and varying side effects from medications compared to men, and the lack of inclusivity of women in clinical studies has been perpetuating this issue for decades. The disparity in drug reactions and usage between men and women is caused by differences in drug disposition as well as psychological habits of drug use.
Sex differences in drug disposition majorly impact male and female reactions to drugs. Drug disposition occurs through separate phases: absorption, distribution, bioavailability, metabolism, and excretion. In general, it has been hypothesized that women who have more subcutaneous lipid content are administered drugs transdermally versus men who are generally administered drugs orally. This difference in administration directly impacts the bioavailability of the drug as oral drugs undergo the first pass effect by the liver before reaching their target organs, ultimately reducing bioavailability. Drugs administered transdermally enter directly into the bloodstream and thus have a much higher onset of action and bioavailability due to the lack of first-pass effect. Additionally, gastric fluid is more acidic in males than females, and the basal and maximal flow of gastric fluid and acid secretion is lower in women than men. These reduced pH levels result in decreased weak acid absorption and weak bases in men, whereas women have increased absorption of these acids. This increased absorption accounts for the increased prevalence of adverse side effects in women versus men. These side effects can range from headaches and nausea to bleeding and seizures.
Similarly, how the drug gets distributed from the blood throughout the body, differs between men and women, which directly correlates to their reactions to the drug. The distribution of a drug is affected by multiple body composition parameters. Sex differences in these parameters correlate to the differences in the drug concentration at the target site. Research shows that total blood volume, red blood cell volume, total body water, extracellular and intracellular water, and plasma volume are more significant in men than women. Thus, if a male and female are given the same dose of a water-soluble drug, the greater the total body water, extracellular water, plasma volume, and intracellular water, the greater the distribution of the drug, thus decreasing the drug’s concentration. Therefore, as the drug gets distributed in a male body, there tends to be lower concentrations in his body compared to women thus resulting in increased adverse effects in women.
Furthermore, as drugs become metabolized within the body, lipid solubility, protein binding, dose, and route of exposure affect the drug’s biotransformation rate within the body. The CYP450 enzymes involved in the enzymatic reactions of the two hepatic drug metabolism phases show sex-related differences. Additionally, basal metabolic rates (BMR) directly affect the metabolism of chemicals within the body. On average, men have a higher BMR than women. Lower BMR per unit body surface area is due to the reduction of lean body mass in women due to their smaller skeletal muscle component. As a result, men will metabolize drugs more quickly than women’s bodies, which will metabolize the drugs more slowly. This will again cause increased adverse effects in women compared to men.
The last factor of drug disposition that accounts for differences in reactions is elimination. Both processes of metabolism and elimination are responsible for drug inactivation. Renal, hepatic, or pulmonary routes eliminate drugs from the body. As a result, drugs can be eliminated from the body through many means, including sweat, breast milk, tears, released air, feces, and urine. Renal or kidney function is essential for the elimination of drugs, as increases in renal blood flow and glomerular filtration will increase the kidney’s elimination rate of a drug. Overall, renal blood flow, glomerular filtration, tubular secretion, and reabsorption are more prominent in men than women. This difference means male bodies excrete drugs more readily than women, which once again contributes to drugs staying in female bodies longer and increasing the risk of adverse effects.
On another note, studies have shown gender differences in the overall usage of medication. Several studies have shown that females generally use medications more often than males. Similarly, results of an interview survey conducted in 2009 revealed that the rate of contact with health professionals within six months was higher among females than males. Additionally, in a study of over three million patients in Southern Italy, data was collected regarding outpatient drug prescriptions collected from administrative databases. The study found that the number of prescriptions was greater in females than males, 55.6% vs. 44.4%, although males were treated longer than females. Across all age groups, the prevalence of prescription rates remains high in females versus males. Among children aged 0-14 years, the prevalence rate was higher in females––59.4% vs. 56%––and these trends remained stagnant with adults aged 25-34 having 55.8% female and 42.3% male prescriptions. These studies were conducted on 1,000 treated patients per day. Some of the drugs that showed this correlation included anti-inflammatory and antirheumatic products, focusing specifically on coxib drugs, as they had the highest prevalence. However, the proportion of sporadic users of anti-inflammatory and antirheumatic products was higher for males than females, 54.4% vs. 47.1%, as observed for the corresponding coxibs discussed.
Although the 2016 NIH requirement for the inclusion of both male and female samples showed hope for change in medicine, much advancement still needs to occur. A new device created by the University of Virginia Health System to simulate male and female livers in order to use them to reveal sex-specific differences in how the tissues are affected by drugs is a revolutionary step towards change. The new model also helps ensure new medications don’t cause harmful side effects. The scientists of UVA, who developed this new tool, conducted studies and found that women consistently reported liver-related adverse events more often than men did. This research led them to develop computer models of the male and female livers that integrated data on gene activity and metabolic processes within the cells. This was a revolutionary step towards the understanding of how drugs affect the tissue differently in men and women.
In conclusion, the disparity in drug reactions and usage between men and women is caused by differences in drug disposition as well as psychological habits of drug use. Throughout the separate phases – absorption, distribution, bioavailability, metabolism, and excretion – male and female physiological differences play a huge role. The main differences result in women experiencing more adverse effects than men; however, with all these disparities, medicine is still behind on the inclusivity of women in clinical drug trials. With devices such as the model to identify sex-specific differences, change is possible, and it is a step towards women being properly dosed for medication and living lives with reduced side effects.