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Try out PMC Labs and tell us what you think. Learn More. Males and females differ in their response to drug treatment. These differences can be critical in response to drug treatment. It is therefore essential to understand those differences to appropriately conduct risk assessment and to de safe and effective treatments.
Even from that modest perspective, how and when we use drugs can result in unwanted and unexpected outcomes. We summarize the sex differences that impact pharmacokinetics and pharmacodynamics and include a general comparison of clinical pharmacology as it applies to men, pregnant and non-pregnant women. Since this is an area rapidly evolving, it is essential for the practitioner to review drug prescribing information and recent literature to understand fully the impact of sex differences in clinical therapeutics. The goal of clinical pharmacology is to understand how to optimize the use of drugs in order to minimize therapeutic adverse event and enhance therapeutic effectiveness.
Both can be achieved by understanding the pharmacokinetics PK and pharmacodynamics PD in the diverse populations in which the drugs use is intended. Circulating drug concentrations are affected by a combination of factors and determine the resulting outcome [ 1 ].
The relationship between dosing and effect is more variable than the relationship between concentration and effect. The main enzymes involved in drug metabolism belong to the cytochrome P CYP group. These are a large family of related enzymes housed in the smooth endoplasmic reticulum of the cell. The CYP isoenzymes discussed in this article are all coded for by autosomal chromosomes. It is plausible that sex-related disparities in pharmacokinetics arise due to variations in the regulation of the expression and activity of CYP isoenzymes, most probably through endogenous hormonal influences.
Sex is the property or quality by which organisms are classified as female or male on the basis of their reproductive organs and functions, while gender is expressed in terms of masculinity and femininity. It is how people perceive themselves and how they expect others to behave, and is largely culturally determined. As our knowledge of medicinal drug toxicology and pharmacology is expanding it has become clear that men and women differ in response to drug treatment.
Women also differ from men in response to occupational exposures [ 2 , 3 ]. The U. General ing Office GAO reviewed the 10 drugs withdrawn from the market during the period January 1, through December and observed that 8 of the 10 were withdrawn because of evidence of greater risks of adverse effects in women.
Table II provides a comparison of some of the suggested reasons for sex differences in adverse event frequencies. Accordingly, it is plausible that given the sex-related differences in pharmacokinetics, women are more frequently overdosed than men. This implies that at a given dose a drug reaches higher free drug concentrations or remains longer in the body in females than in males.
Alternatively, females may be more sensitive to drugs than males. In this instance, free drug concentrations and duration in the body would be similar in men and women but women would respond to a greater extent. Yet, another plausible explanation might be attributed to behavior; if women take a greater of medications than men they can increase the incidence of adverse events resulting from drug interactions. Typical drug interactions are due to alterations in PK — in this instance the consequence would be an increase in the free drug concentration or a decrease in the rate of drug clearance.
An additional reason for higher rates of adverse events reported in women may be due to higher reporting rates from women than men. Finally, it is also possible that sex differences between men and women result in similar rates of adverse events but women experience more severe events. 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 any difference in the way men and women respond to a product.
The report supported studying potential sex differences during drug development. Unfortunately, substantial gaps still remain in the inclusion of women in clinical studies. As a result, care givers are often left having to estimate the appropriate dose, dosing schedule and treatment interval without or with only modest knowledge of the appropriate use of the drug or their drug of choice in pregnant women or women in general.
The factors influencing absorption are route-specific oral, dermal, rectal, vaginal, intramuscular, intravenous, intraarterial, intrathecal, intraperitoneal and may also be sex-specific. Chemicals or drugs cross body surfaces such as the gastrointestinal tract, respiratory tract, or skin different in males and females to enter the systemic circulation. The absorption rate and extent of a drug are drug-specific. Examples of drugs that illustrate sex differences in drug absorption include rifampicin, benzylamine and IM cephradine [ 4 — 6 ]. In general oral drug administration is the route of choice in the daily practice of pharmacotherapy, and especially in outpatient setting.
Ingestion, food interactions e. It has been hypothesized that women, by virtue of having greater subcutaneous lipid content, receive different doses of transdermally administered drugs. Women may also take in less of inhaled aerosol drugs such as ribavirin and cyclosporine, although only limited data are yet available. Gastric alcohol dehydrogenase activity is higher in males than in females [ 7 ].
As a result, women have a lower alcoholic toxic threshold than men and develop alcoholic liver injury more rapidly [ 8 ]. In addition, estrogens have a major influence on the susceptibility of Kupffer cells to gut-derived lipopolysacharride differences in gastric first-pass metabolism, elimination rate, or alcohol distribution volume.
The enterocytes express ificant levels of CYP3A isoenzymes which contribute ificantly to the first pass metabolism of many orally administered drugs and have known sex differences. Multi-specific transporters are involved in hepatobiliary and urinary excretion.
Tissue distribution and elimination pathways of drugs are explained by the similarity and differences in the substrate recognition by transporters expressed in the liver and kidney. Variability in intestinal expression of enzymes that modulate gut transport of drugs may result in sex-based variability in plasma drug concentrations. For example, p-glycoprotein PGP , membrane ATPase transporter protein found in high concentrations in the enterocytes of the small intestine is encoded by the multi drug resistance transporter-1 gene MDR1 expressed in the human intestine, liver and other tissues [ 9 ].
Cardiac output CO and regional distribution of blood flow are two important parameters that impact pharmacokinetics, especially absorption. Because CO is related to body size it is best normalized to surface area; when normalized, men and women have similar mean cardiac indices of 3. Reduced pH in decreased absorption of weak acids and increased absorption of weak bases. Drug absorption occurs at different sites along the gastrointestinal tract including stomach, small and large intestines. The rate of absorption is influenced by multiple factors, including gut transit times, lipid solubility of the agent, pH at the site of absorption, ionization and molecular weight of the agent, and gut motility.
Transit times differ ificantly in men and women [ 11 ] ; mean transit times being shorter in men While fiber ingestion decreases the transit time, female gut transit times are consistently longer. The kidneys are responsible for the maintenance of water and electrolyte balance, the synthesis, metabolism and secretion of hormones, and for excretion of waste products from metabolism as well as most drugs, hormones, and xenobiotics. The human kidney demonstrates sex-related differences in the subunits of glutathione-S-transferase isoenzyme GST [ 12 ].
Iron and ethanol are two important chemicals that have ificant differences between males and females in gastrointestinal absorption summarized in Table IV. Men metabolize ethanol more rapidly in the gut making ethanol less available for absorption. Once absorbed, most drugs bind to plasma proteins specific for some aspect or structural feature of the drug.
The distribution of a drug is affected by multiple body composition parameters Table V. Sex-differences in these parameters may for differences in the concentration of a drug at the target site and result in varying responses. On average, total body water, extracellular water, intracellular water, total blood volume, plasma volume, and red blood cell volume are greater for men than women.
Therefore, if an average male and an average female are exposed to the same dose of a water soluble drug, the greater total body water, plasma volume, extracellular water, and intracellular water will increase the volume of distribution thus decreasing drug concentration. As an example, the smaller volume of distribution for ethanol in women than men produces higher peak concentrations from the same dose Table IV. Regional blood flow can impact pharmacokinetics; The reference values for resting blood flow to organs and tissues for typical 35y males and females show ificant differences for resting blood flow as a percentage of CO to skeletal muscle greater for men and adipose tissue greater for women.
These differences may reflect sex-based differences in the percentage of total body mass represented by each tissue [ 13 ]. The main binding proteins for various drugs in plasma are albumin, alpha-1 acid glycoprotein AAG and alpha globulins. AAG levels and AAG-glycosylations vary in association with endogenous and exogenous estrogen inducing hepatic glycosylation of these proteins thus decreasing plasma AAG levels, while albumin concentrations do not consistently vary by sex [ 14 ]. Estrogens also increase the levels of the serum-binding globulins sex-hormone binding globulin, corticosteroid binding globulin, and thyroxine binding globulin [ 15 ].
Sex-related differences in plasma binding of selected compounds are listed in Table VI. Variations in levels of plasma binding can alter the free active fraction of drugs. Body fat as a percentage of total body weight is higher in women than men and increases by age in both sexes [ 16 ]. The total body fat for an adult reference male is The larger proportions of body fat in women, and especially in pregnant women, may increase the body burden of lipid-soluble, slowly metabolized toxicants.
Differences in body fat and in organ blood flow in women have been implicated in the faster onset of action and prolonged duration of neuromuscular blockade in women e. Differences in body fat content and in protein binding are responsible for sex-related pharmacokinetic differences in the distribution of diazepam [ 20 ]. Cardiac output CO and regional distribution of flow are important for pharmacokinetics. CO is commonly standardized and reported as the cardiac index CI. The distribution of CO, or regional blood flow, is similar for men and women for some organs adrenal 0.
Drug metabolism and biotransformation occurs predominantly in the liver, as well as in extra hepatic sites of metabolism such as the lung, kidney, intestinal tract, and skin Table VII. During pregnancy, biotransformation can also occur in the placenta and in fetal tissues. Lipid solubility, protein binding, dose, and route of exposure all affect the rate of biotransformation. Sex differences in pharmacokinetics: biotransformation Physiological parameters which may influence differences in metabolism. Weight for individuals of a given height will produce overlap in the BMR distributions for men and women.
However, sex-dependent differences in biotransformation have been observed for a few specific drugs such as nicotine, chlordiazepoxide, flurazepam, acetylsalicylic acid, and heparin [ 22 , 23 ]. Hepatic clearance of drugs is a function of liver blood flow and hepatic enzyme activity.
Ingested compounds may remain unchanged and possibly accumulate in a storage compartment , or, based on their degree of lipophilicity and polarity, be subject to metabolism. Hepatic drug metabolism is divided into two, usually sequential enzymatic reactions: Phase I and Phase II reactions. However, even if there are sex-differences in drug pharmacokinetics, only some drugs have shown ificantly higher plasma concentrations in women.
A comprehensive review of second-generation atypical antipsychotics SGAs concludes that sex differences in adverse effects have not been well studied, but some adverse effects such as weight gain, hyperprolactinemia and cardiac effects are particularly problematic for women [ 25 ]. Most studies reviewed indicate that clozapine and olanzapine are associated with greater bodyweight gain than other atypical antipsychotics, and that serious adverse effects such as metabolic syndrome, which includes increased visceral adiposity, hyperglycemia, hypertension and dyslipidaemia induced by SGAs, are more frequent in females.
Although women are at a lower risk of sudden cardiac death, they have a higher risk of induced long QT syndrome from antiarrhythmic and, probably, antipsychotic drugs. Metabolism of chemicals may be estimated by basal metabolic rates BMR.
For all ages, on average, men have a higher BMR than women.Ladies looking for sex Anderson SC
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