Physiological, hormonal, and genetic differences between males and females affect the prevalence, incidence, and severity of diseases and responses to therapy. Understanding these differences is important for designing safe and effective treatments. This paper summarizes sex differences that impact drug disposition and includes a general comparison of clinical pharmacology as it applies to men and women.
At the core of personalized medicine is the identification of factors influencing disease processes and therapy [
Many factors influence circulating drug concentrations, as well as the concentrations at the sites of action, and determine the resulting outcome [
Gender, a social construct, is expressed in terms of masculinity and femininity. It is defined by the way people perceive themselves and how they expect others to behave. Gender is largely determined by culture. Sex differences result from the classification of organisms based on genetic composition as well as reproductive organs and function [
Since pharmacokinetics, pharmacodynamics, and responses during clinical trials differ between men and women, U.S. FDA regulations and guidance are in place to ensure that both sexes are represented in all phases of clinical trials and that medical products are labeled to alert physicians and patients to sex differences in drug responses. In 1999, the National Institutes of Health published the “Agenda for Research on Women’s Health for the 21st Century,” concluding that sex-related differences in pharmacokinetics and pharmacodynamics must be further assessed.
In an effort to overcome gaps in knowledge regarding the actions of drugs in women, more women are now included in clinical trials. The NIH Biennial Report of the Director of 2006-2007 reported that in 2006, of 624 extramural and intramural phase III clinical research protocols (499,430 participants), 63% were women [
The FDA Adverse Events Reporting System (AERS) is a voluntary database of adverse events. Based on an analysis of AERS data and other data resources, women experience more adverse events than men, and in general, these adverse events are of a more serious nature [
Sex-related differences in the frequencies of adverse events reporting may be due to pharmacokinetic or pharmacodynamic factors, polypharmacy, or differences in reporting patterns [
Suggested reasons for sex differences in adverse event reporting.
Reason for sex difference | Pharmacological reason | Pharmacological factors |
---|---|---|
Women are overdosed | Pharmacokinetics | Sex differences in volume of distribution |
Women are more sensitive | Pharmacodynamics | Sex differences in drug targets |
Women are prescribed multiple medications | Drug-drug interactions | Drug-drug induced alterations |
(Table modified from Soldin and Mattison [
Drug absorption and bioavailability are influenced by drug- and route-specific factors (oral, dermal, rectal, vaginal, intramuscular, intravenous, intra-arterial, intrathecal, and intraperitoneal). Routes of absorption occur across body surfaces, such as the gastrointestinal tract, respiratory tract, or skin, which differ in males and females. For example, drug absorption occurs at different sites throughout the gastrointestinal tract, and rate of absorption is influenced by gut transit times, lipid solubility of the agent, pH at the site of absorption, and the ionization and molecular weight of the agent [
The FDA evaluated sex differences in bioequivalence among 26 studies submitted to the agency between 1977 and 1995 [
Other investigators have utilized multidrug cocktails to assess bioavailability and metabolism across age and sex [
In addition to sex differences in bioavailability, it is important to consider that food interactions (e.g., grapefruit juice), gut motility and transit time, gut pH, biliary secretion and gut flora, enterohepatic circulation and oral contraceptives can differentially influence the bioavailability of a drug in men and women [
An important part of bioavailability includes the gastric and hepatic enzymes and transport proteins that oral drugs interact with prior to reaching the systemic circulation [
Transport proteins play a critical role in transporting drugs into and out of all cells and are consequently involved in hepatobiliary and urinary excretion [
Sex differences are also exhibited by the serotonin 5-HT1A receptor and serotonin transporter (5-HTT), which is a target for selective serotonin reuptake inhibitors (SSRIs), psychotropic drugs used in the treatment of depression, anxiety, and personality disorders. Women have significantly higher 5-HT1A receptor and lower 5-HTT binding potentials throughout the cortical and subcortical brain regions and exhibit a positive correlation between 5-HT1A receptor and 5-HTT binding potentials for the hippocampus. Thus, sex differences in 5-HT1A receptor and 5-HTT binding potentials may result in biological distinctions in the serotonin system, thereby contributing to sex differences in the prevalence of psychiatric disorders such as depression and anxiety [
Gastric fluids are generally more acidic in males than females (pH 1.92 versus pH 2.59), and basal and maximal flow of gastric fluid and acid secretion are both higher in men [
The kidneys are responsible for the maintenance of water/electrolyte balance, the synthesis, metabolism, and secretion of hormones, and excretion of waste products from metabolism as well as most drugs and xenobiotics. The human kidney demonstrates sex-related differences in the subunits of glutathione-S-transferase isoenzyme [
Iron also has significant differences between males and females in gastrointestinal absorption. In preadolescent males and females, it has been shown that 45% of ingested iron is incorporated into erythrocytes by females compared to 35% in males (iron-regulated surface determinant −0.78) [
Once absorbed and in the circulation, most drugs bind to plasma proteins. Distribution is a function of multiple physiologic and body composition characteristics. Sex differences in these parameters may account for differences in the concentration of a drug at the target site and result in varying responses. However, differences in protein binding between men and women are generally rare, and there is still no convincing link between protein-binding differences and sex-specific ADRs, with the exception of lignocaine and diazepam [
For lipid-soluble drugs, there is generally an increased
Sex differences in blood distribution and regional blood flow can also impact pharmacokinetics. In general, the reference values for resting blood flow to organs and tissues for 35-year-old males and females show significant differences as a percentage of cardiac output. For example, blood flow to skeletal muscle is greater for men and to adipose tissue is greater for women. These differences may reflect sexbased differences in the percentage of total body mass represented by each tissue [
The main binding proteins for various drugs in plasma are albumin,
Sex differences in plasma binding.
Compound | Description |
---|---|
Testosterone | Plasma protein binding: F > M, Estrogen increases |
Chlordiazepoxide | Plasma protein binding: M > F > Foc |
Diazepam | Free fraction: Foc (1.99%) > F (1.67%) > M (1.46%) |
Lidocaine | Free fraction: F (34%), M (32%) < Foc (37%) |
Warfarin | Free fraction: F > M |
Morphine, Phenytoin Oxazepam, Lorazepam | No differences |
oc: oral contraceptives.
Table modified from Soldin and Mattison [
Therapeutic drug monitoring is the measurement of specific drugs in order to maintain a relatively constant circulating drug concentration. Drugs that are monitored tend to have a narrow “therapeutic range”—the drug quantity required to be effective is not far removed from the quantity that causes significant side effects and/or signs of toxicity. Maintaining drug concentrations within the therapeutic range is not as simple as giving a standard dose of medication. Often, if the free fraction increases, there is a shift of the drug to the tissues/target or resultant higher clearance, with the total concentration not changing, for example, phenytoin.
Body fat as a percentage of total body weight is higher in women than in men and increases by age in both sexes [
Several studies have observed that when dose is corrected by body weight, some of the sex differences seen in pharmacokinetics disappear [
Cardiac output and regional distribution of flow are important for drug disposition. Cardiac output is commonly standardized and reported as the cardiac index, which is similar for both sexes between 18 and 44 years of age. The distribution of cardiac output, or regional blood flow, is similar for men and women for some organs (adrenal 0.3%, bone 5%, brain 12%, lung 2.5%, skin 5%, and thyroid 1.5%, reported as percent of cardiac output) and different for others (adipose: male = 5%, female = 8.5%; heart: male = 4%, female = 5%; kidney: male = 19%, female = 17%; liver: male = 25%, female = 27%; muscle: male = 17%, female = 12%), reflecting sex-based differences in body composition [
Drug metabolism (biotransformation) occurs predominantly in the liver, as well as in extrahepatic sites such as the intestinal tract, lung, kidney, and skin. Hepatocytes and intestinal cells express significant levels of CYP3A and phase II enzymes such as uridine diphosphate glucoronosyltransferase (UGT), which may significantly contribute to the first pass metabolism of many orally administered drugs (see discussion above on bioavailability). Lipid solubility, protein binding, the dose, and the route of exposure all affect the rate of biotransformation.
Despite the large variations in drug metabolism among individuals, correction for height, weight, surface area, and body composition eliminates some but not all of the “sex-dependent” differences. However, sex-dependent differences in biotransformation have been observed for drugs such as nicotine, chlordiazepoxide, flurazepam, aspirin (acetylsalicylic acid), and heparin [
The main enzymes involved in drug metabolism belong to the CYPs. These are a large family of related enzymes housed in the smooth endoplasmic reticulum of the cell. While the CYP enzymes discussed in this paper are all coded for by autosomal chromosomes, it is possible that sex-related disparities in pharmacokinetics arise from variations in the regulation of the expression and activity of CYP enzymes through endogenous hormonal influences. For reviews that deal specifically with CYP enzymes, please refer to [
Ingested compounds may remain unchanged (and possibly accumulate in a storage compartment) or, based on their degree of lipophilicity and polarity, they may be subject to metabolism. Hepatic drug metabolism is divided into two usually sequential enzymatic reactions: phase I and phase II reactions. Some of the CYP enzymes show clear sex-related differences (Table
Sex differences in hepatic clearance by route of metabolism/elimination.
Metabolic route | Model substrates | Drugs metabolized by route | Sex-specific activity |
CYP1A | Caffeine, nicotine paracetamol (acetaminophen) | Clomipramine, clozapine, olanzapine, paracetamol, tacrine, theophylline | |
CYP2C9 | Dapsone, ( | Ibuprofen, ( | |
CYP2C19 | ( | Lansoprazole, omeprazole, hexobarbital, mephobarbital, citalopram, celecoxib, irbesartan, imipramine, piroxicam, propranolol (in part) | |
CYP2D6 | Dextromethorphan, debrisoquine, sparteine | Codeine, encainide, flecainide, fluoxetine, hydrocodone, metoprolol, paroxetine, mexilitine, phenformin, propranolol, sertraline, timolol, haloperidol, clomipramine, desipramine, imipramine, propafenone, testosterone | |
CYP2E1 | Chlorzoxazone | ||
CYP3A | Midazolam, dapsone, cortisol, Lidocaine, nifedipine, erythromycin | Alprazolam, alfentanil, astemizole, atorvastatin, carbamazepine, cisapride, clarithromycin, cyclosporin, cyclophosphamide, diazepam,diltiazem, erythromycin, estradiol, fentanyl, indinavir, itraconazole, ketoconazole, lovastatin, quinidine, nimodipine, nisoldipine, quinidine, ritonavir, verapamil, tacrolimus, simvastatin, vincristine, vinblastine, tamoxifen, tirilazad, troglitazone | |
Metabolic route | Model substrates | Drugs metabolized by route | Sex-specific activity |
UDP-glucuronosyl-transferases | Caffeine | Clofibric acid, diflusinal, ibuprofen, mycophenolate, mofetil, paracetamol, zidovudine | |
Sulfotransferases | Caffeine | — | |
N-Acetyl-transferases | Caffeine, dapsone | Catecholamine derivatives, mercaptopurine, isoniazid, hydralazine | |
Methyl-transferases | Norepinehrine, epinephrine | Azathioprine, dopamine, levodopa, 6-mercaptopurine, thioguanine, tazathioprine |
Table modified from Soldin and Mattison [
Sex-related differences have been shown for some CYPs, with a higher activity in females for CYP3A4 (Table
By studying the activity of sex hormones, as a consequence of physiological, pathological, or pharmacological manipulations, researchers now believe that many of the changes seen in CYP enzymes may be gender specific [
Antihistamines, in particular, have been shown to exhibit sex-specific differences in pharmacokinetics. They act as CYP2D6 substrates, which have been shown to exhibit slower metabolic elimination in women. This may explain why women are more vulnerable to sedation and drowsiness effects of antihistamines than men. Gender differences in PGP expression in the brain may also underlie the sedative side effects often experienced by women [
However, even if there are true sex differences in drug pharmacokinetics, only few drugs exhibit significantly different plasma concentrations in women. A comprehensive review of second-generation (atypical) antipsychotics concludes that even though sex differences in cases of adverse events have not been well studied, some adverse effects such as weight gain, hyperprolactinemia, and cardiac effects, are particularly problematic for women [
Metabolism of chemicals may be estimated by basal metabolic rates. For all ages, on average, men have a higher basal metabolic rate than women. Since the metabolism of adipose tissue differs from that of muscle tissue, some of the differences between men and women are attributable to body composition metabolism of adipose tissue [
Hepatic clearance of drugs is a function of liver blood flow and hepatic enzyme activity. Although cardiac output and hepatic blood flow are lower in women than in men normalized per m2/kg, sex differences in hepatic enzymes also play a major role in determining sex-related pharmacokinetic activity. At the canalicular surface of hepatocytes, PGP will direct the biliary excretion of certain drugs, and its expression has been found to be twofold lower in women than in men. Consequently, women display increased and sustained intracellular concentrations of PGP substrates, increased activity of hepatic drug-metabolizing enzymes, and thus increased clearance of the drug [
Two processes, metabolism and elimination, are responsible either separately or together for drug inactivation. Without these means, drugs would continuously circulate throughout our bodies, bind to various receptors, and interrupt important physiological processes. Drugs are generally eliminated from the body by renal, hepatic, or pulmonary routes. Consequently, drugs may be eliminated from the body in sweat, tears, breast milk, and expired air. The most common routes are via feces and urine.
The kidney is the major organ of drug excretion of either the parent drug compounds or drug metabolites. There are known sex differences in all three major renal functions-glomerular filtration, tubular secretion and tubular reabsorption. Renal clearance is generally higher in men [
Renal function is important for elimination. Chemicals can be excreted into the urine through glomerular filtration, passive diffusion, and active secretion. Increases in renal blood flow and glomerular filtration increase the elimination rate of drugs cleared by the kidneys. When standardized for body surface area, renal blood flow, glomerular filtration, tubular secretion, and tubular reabsorption are all greater in men than in women [
Sex-dependent differences among the three primary opioid receptor subtypes—mu, delta, and kappa—have been extensively studied. The kappa opioid receptor subtype may be sex-dependently modulated by
Sex differences in pharmacokinetics of self administered drugs and in drug dependence have also been explored. Biologically, it is believed that sex and gonadal hormones underlie many of the differences seen in drug sensitivity, addictive behavior, and susceptibility to drug abuse. In general, women appear to be more vulnerable to the rewarding and dependent properties of cannabinoids, alcohol, opioids, and cocaine. Many animal models of gender influences on substance abuse have confirmed clinical findings [
For cortisol and first-generation antihistamines, there appears to be significant sex differences in pharmacodynamics. Because women are more sensitive to cortisol suppression, they may also be more sensitive to the effects on basophils and helper T lymphocytes [
There are numerous examples supporting the contention that female sex hormones impact drug-metabolizing pathways. For example, drug-induced long QT syndrome has a higher rate of incidence in females, particularly during the ovulatory phase of the menstrual cycle compared to the luteal phase [
Estrogen has membrane, cytosolic, and nuclear targets [
Increased levels of estrogen and progesterone alter hepatic enzyme activity, which can increase drug accumulation or decrease elimination of some drugs. Female steroid hormones and prolactin play a role in autoimmunity. Regulation of immunity and interactions between the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes contribute to the 2- to 10-fold incidence and severity of autoimmune/inflammatory diseases in females compared to males. Most autoimmune diseases are detected in females of childbearing age. Metabolic changes can also depend on hormone levels that change during the menstrual cycle, with use of oral contraceptives, throughout pregnancy, or during menopause. For example, some asthmatic women have worsening symptoms before or during menstruation [
Although sex hormones are thought to play a dominant role in modulating sex-based differences in pharmacokinetics, studies examining this have yielded conflicting results. Midazolam clearance (reflecting CYP3A4 metabolic activity) failed to show fluctuations during the menstrual cycle [
There are conflicting data that exist on pharmacokinetic changes in women relating to menopausal status. To examine menopause-related alterations in intestinal or hepatic CYP3A4 activity, several studies compared the pharmacokinetics of midazolam, erythromycin, and prednisolone clearance in pre- and postmenopausal women and found no significant differences in drug metabolism according to menopausal status [
Data acquired on sex differences in absorption, distribution, metabolism and elimination allow exploration of sex differences in disposition and response to chemicals and drugs. Results from clinical trials focusing on HIV-infected female subjects have suggested that there are clinically relevant sex-related differences in the efficacy and safety of drug treatment (Table
Some drugs that display sex differences in pharmacokinetics.*
Drug | Pharmacokinetic parameter | Comments |
---|---|---|
Acebutolol [ | Area under the concentration-time curve | The concentration-time profile is larger in women, suggesting greater therapeutic and potential side effects |
Aspirin [ | Clearance, half-life | Aspirin is cleared more rapidly from women |
Benzylamine | Following transdermal absorption, women excrete 3 times more than men | |
Beta-Blockers; | Oral clearance lower in women, lower volume of distribution in women resulting in higher systemic exposure | The greater reduction in blood pressure in women was due to pharmacokinetic and not pharmacodynamic differences |
Cefotaxime [ | Clearance | Clearance is decreased in women |
Ciprofloxacin [ | Clearance | Clearance is lower in women |
Cephradine [ | Slower rate of absorption and lower bioavailability in the female; increased clearance and decreased terminal elimination half-life in pregnancy | |
Clozapine [ | significantly higher plasma levels for women | |
Diazepam [ | Plasma binding | Larger volume of distribution in women |
Ethanol [ | Volume of distribution, clearance, and first-pass metabolism | When ethanol is ingested, men metabolize more in first pass metabolism; in addition the volume of distribution is smaller in women |
Ferrous Sulfate | Absorption | Absorption higher in prepubertal girls than boys |
Fluoroquinolones [ | Volume of distribution | Lower in women |
Gemcitabine [ | Clearance | Clearance is lower in women |
Heparin [ | Clearance | Clearance is lower in women |
Iron [ | Absorption measured as % of the dose incorporated into red blood cells | More ingested iron is absorbed by women than men |
Methylprednisolone [ | Plasma binding, clearance, volume of distribution, and half-life | Plasma binding and |
Metronidazole | Volume of distribution | Smaller volume of distribution and increased clearance resulting in lower AUC in women |
Metoprolol [ | Plasma binding, clearance, volume of distribution, half-life | Clearance increases during pregnancy, but is smaller in women; |
Midazolam [ | Considered to be probe for CYP3A4, not substrate for PGP | No sex difference in clearance following either oral or intramuscular administration; interpretation complicated by |
Mizolastin [ | Oral availability | Longer duration for absorption in men, contributing to variability in drug concentrations in men and women |
Naratriptan [ | Oral availability, peak concentration | Oral bioavailability being greater in women results in peak concentration is higher in women than men |
Ofloxacin | Clearance | Clearance is lower in women |
Olanzapine [ | Higher activity in women for CYP3A4 and CYP2D6 | Significantly higher plasma levels for women |
Ondansetron [ | Oral availability, clearance | Oral availability is increased in women |
Phenytoin [ | Plasma binding | |
Prednisolone [ | Distribution | Oral clearance and volume of distribution significantly higher in men |
Propranolol [ | Plasma binding, clearance, volume of distribution, and half-life | Plasma binding is similar among men and women; however, plasma binding increases during pregnancy. Clearance is smaller in women. |
Quinine [ | Plasma binding, clearance, volume of distribution, and half-life | Plasma binding is unaltered during pregnancy, as is clearance. |
Rifampicin [ | Women absorb the drug more efficiently | — |
Rizatriptan [ | Urinary excretion, clearance, volume of distribution, half-life | Urinary excretion is similar in men and women; clearance is greater in men |
Rocuronium | Distribution | Prolonged drug duration due to higher fat content and lower organ blood flow in women |
Salicylate [ | Absorption | Increased rates of absorption in women |
Selective Serotonin | Plasma concentrations are higher in women | Decreased metabolism by hepatic CYP |
Vecuronium | Distribution | Prolonged drug duration due to higher fat content and lower organ blood flow in women |
Verapamil; Calcium channel blocker [ | Clearance following intravenous administration more rapid in women, but oral clearance higher in men than women. Substrate for both CYP3A4 and PGP | Sex differences in hepatic and gut CYP3A4 and PGP lead to complex differences in clearance between men and women. Bioavailability from the gut is greater in women. The greater bioavailability leads to increased systemic exposure in women |
Oral clearance is lower in women |
*Pregnancy-related PK changes are in
Table modified from Soldin and Mattison [
Males and females may differ in specific drug pharmacokinetics and pharmacodynamics. It is, therefore, essential to understand those sex differences in drug disposition and response, as they may affect drug safety and effectiveness. To minimize therapeutic adverse events, clinicians and the pharmaceutical industry must establish clear therapeutic goals for the drugs of choice prior to treatment of women. It must be determined if the treatment should be assessed by clinical signs and symptoms or by laboratory test results whether drug toxicity will be evaluated by clinical or laboratory assessment, and what determines the appropriate duration of treatment. Furthermore, clinicians should be aware of and understand the principles of clinical pharmacology and absorption, disposition, metabolism, and elimination as they apply to the drug of choice. In particular, the prescribing physician should understand the relationship between drug dose, drug concentration and desired biological effect at the action site, the mechanism of action of the drug, the impact of the chosen drug on the patient’s signs, symptoms of adverse effects, and laboratory testing.
In general, data on sex differences are mostly obtained by
Alpha-1 acid glycoprotein
Adverse Drug Reactions
Adverse Events Reporting System
ATP-binding cassette
Absorption, distribution, metabolism, and excretion
Basal metabolic rates
Cardiac output
Cytochrome P450-3A
Elimination rate
Food and Drug Administration
General Accounting Office
Glomerular filtration rate
Glutathione-S-transferase isoenzyme
Hypothalamic-pituitary-adrenal
Hypothalamic-pituitary-gonadal
Institute of Medicine
Multidrug resistance transporter-1
National Institutes of Health
Organic anion transporting polypeptide
H+/ditripeptide transporter
p-glycoprotein
Second-generation (atypical) antipsychotics
Selective serotonin reuptake inhibitors
Uridine diphosphate glucoronosyl transferase.
The authors declare no conflict of interests.
Dr. Soldin is partially supported by NIH/NICHD-supplement to the Obstetric-Fetal Pharmacology Research Unit Network Grant 5U10HD0478925, funds from the Office of Research on Women’s Health and FAMRI Clinical Innovator Award.