Sex Differences in Other Pharmacokinetic Parameters
Sex differences are also found in other pharmacokinetic parameters such as drug absorption, drug distribution, and excretion.
Drug Absorption
A well-known example is the faster alcohol absorption in women than in men. Alcohol dehydrogenase, the gastric mucosal enzyme responsible for alcohol oxidation, is less active in women than in men. Therefore, women have higher peak blood concentration and subsequently faster absorption of alcohol after its consumption. They are also more susceptible to both acute and chronic effects of alcohol when compared to men.
The gastrointestinal (GI) transit rate can affect the plasma concentrat ion and absorption of orally taken drugs. Since women have slower gastric motility and intestinal transit than men, they may need to wait longer between food consumption and medication if a drug is to be taken on an empty stomach. Captopril, felodipine, ampicillin, demeclocycline, and loratadine are some example drugs.
P-glycoprotein (Pgp), also known as multidrug resistance protein, is a membrane ATPase transporter protein located in the intestine, liver, and kidney, mediating drug efflux and reducing drug absorption from the GI tract. Hepatic expression of Pgp is higher in men, leading to faster transport and shorter elimination half-life of drugs including quinidine and digoxin, which are substrates of this transporter. The lower expression of Pgp, and the subsequent higher plasma concentration of digoxin, may explain the higher mortality rate from digoxin treatment among women patients with heart failure. Concomitant hormonal replacement therapy in women can also lead to such higher risk, as progesterone can inhibit Pgp and thus decrease the excretion of digoxin. Since a retrospective analysis showed no increase in mortality among women when digoxin was maintained at low serum concentrations, administration of lower digoxin doses and monitoring of its serum concentrations have been suggested for women.
Drug Distribution
Compared to men, women have a higher percentage of body fat but lower body water content, which can affect the volume of distribution (Vd) of certain drugs. For lipophilic drugs such as opioids and benzodiazepines, the Vd is usually higher in women. Upon accumulation in the body fat, which acts as a reservoir, the half-life of these lipophilic drugs is extended in women. Chronic dosage can further increase the load in the fatty tissues, with the potential consequence of toxic effects. Thus, it is logical to administer lower dosages of benzodiazepines to women than to men. Since body fat can increase disproportionately with age among women, the sex-dependent disparities in lipophilic drug distribution may also increase with age.
Conversely, Vd for water-soluble drugs such as muscle relaxants is lower in women, leading to a higher initial plasma concentration. Women also show a 20% to 30% greater sensitivity for the muscle-relaxing effects of vecuronium, rocuronium, and pancuronium. Therefore, a dosage reduction of muscle relaxant is necessary for women if shorter drug duration is the goal (i.e., during anesthesia).
Excretion
Both renal blood flow and glomerular filtration rate (GFR) are higher in men than in women. Therefore, women show a slower clearance of drugs that are actively eliminated via the kidney. Examples of these drugs include digoxin, methotrexate, gabapentin, and pregabalin.
Other Factors
Differences in body weight, cardiac output, plasma volume, and regional blood flow between men and women can also lead to sex differences in drug disposition. For example, the plasma concentration of aliskiren, an antihypertensive renin inhibitor, is usually lower in men than in women, but a previous study showed the gender difference could be eliminated when plasma concentration was adjusted for overall body weight. Therefore, clinical dosages of certain drugs may require an adjustment for body weight.
Pharmacokinetics of drugs can be significantly altered during pregnancy due to changes in drug distribution (increased plasma volume and total body water), absorption (prolonged gastric emptying), metabolism (changes in CYP and UGT activity), and excretion (increased GFR). As a result of preexisting conditions (e.g., epilepsy, hypertension) or pregnancy-related complications (e.g., gestational diabetes, severe nausea), a majority of pregnant women take at least one drug. As an example, pregnant women taking lamotrigine for epilepsy have shown increased seizures because the increased metabolism by UGT and subsequent faster clearance of lamotrigine during pregnancy have resulted in subtherapeutic drug concentrations.
Furthermore, use of combined estrogen-progesterone oral contraceptives can have profound effects on pharmacokinetics by reducing the plasma albumin level, increasing or inhibiting the activity of CYP enzymes (Table 1), and increasing the activity of UGTs. Therefore, it is important for clinicians to understand the pharmacokinetic changes of drugs during pregnancy or the use of oral contraceptives and properly readjust the dosage when necessary to avoid over- or underdosing female patients.
Likewise, significant hormonal changes and hormonal replacement therapy in menopausal and postmenopausal women can also lead to altered drug disposition in women. Therefore, dosage optimization may also be needed to maintain drug efficacy and safety in these subgroups. In contrast, the steady plasma level of androgens in adult men has minimal effects on drug pharmacokinetics.
Overall, the physiological differences between men and women result in gender-related peculiarities beyond pharmacokinetics. A recent study on antiplatelet therapy has also shown that women may show different benefits possibly due to their unique hormonal mechanism and platelet biology.