US Pharm. 2014;39(9):40-43.
ABSTRACT: In most clinical trials, women are underrepresented, and gender-specific analysis is uncommon. Sex differences in metabolism (phase I and II) are believed to be the major cause of differential pharmacokinetics between men and women. Many CYP450 enzymes (phase I metabolism) show a sex-dependent difference in activity. Most of the phase II enzymes have a higher activity in men than in women. Activities of these enzymes can also change during pregnancy and with the use of oral contraceptives. Sex differences are also found in other pharmacokinetic parameters such as drug absorption, drug distribution, and excretion. Despite these differences between men and women, sex-specific dosing recommendations are absent for most drugs. Therefore, when a woman consistently experiences less therapeutic effect or more adverse effects from a drug, a change in its dosing regimen may be necessary.
The differences in pharmacokinetics and the subsequent differential susceptibility to adverse drug effects (ADEs) between men and women have gained more awareness in recent years. For example, to reduce the risk of morning-after activity impairment in women, the FDA has recommended lowering the dosages of zolpidem products (Ambien, Edluar, Zolpimist) by 50% for women.1,2 A systematic evaluation of 14 studies showed that women are more affected than men in driving after taking zolpidem (10 mg) the previous night.3 This gender-specific adverse effect is due to a slower clearance of zolpidem in women, who have shown a significantly higher serum concentration of zolpidem than men.2,4
Underrepresentation of Women in Clinical Trials
Historically, women were less enrolled in clinical trials because both pharmacokinetics and pharmacodynamics of a drug can be influenced by menstrual cycle phases, hormonal fluctuations, use of oral contraceptives and hormonal therapy, and life events such as pregnancy and lactation. The number of trials enrolling women has increased after an FDA request to include a fair representation of both genders as participants, but overall, women are still underrepresented.5-8 Additionally, a gender-specific analysis is usually not included in the evaluation of most trial results.5 Among the limited number (~7%) of New Drug Applications (NDAs) that included a sex analysis, there was at least a 40% difference in pharmacokinetics between men and women, but no differential dosing recommendations have been made for these drugs despite the difference.9
Sex Differences in Metabolism
Sex-based differences have been found in four pharmacokinetic areas: absorption, distribution, metabolism, and elimination.10 Among these parameters, sex differences in metabolism are believed to be the major cause of differential pharmacokinetics between men and women.11
Drug metabolism consists of phase I and phase II reactions. Phase I metabolism, mediated mainly by hepatic CYP450, consists of hydrolysis, oxidation, or reduction of drugs. Phase II metabolism attaches a polar group (e.g., glucuronic acid, sulfate, acetyl) to the parent drug or phase 1 metabolite to facilitate renal excretion. It is mediated by enzymes such as uridine diphosphate (UDP)-glucuronosyltransferases (UGTs), sulfotransferases, N-acetyltransferases, or methyltransferases.12,13
Phase I Enzymes: The CYP450 superfamily of enzymes is responsible for metabolizing 70% to 80% of all prescribed drugs.14 A total of 18 CYP gene families have been identified, and the majority of drug metabolism is mediated by CYP1, CYP2, and CYP3.5,15 TABLE 1 shows examples of these CYP enzymes and their known gender-specific activity, which can cause a difference in overall therapeutic effects and ADEs between men and women.16-24 The following are a few examples.
CYP1A2, the primary enzyme for metabolizing the antipsychotic drugs olanzapine and clozapine, shows a higher activity in men. Therefore, clearance of these antipsychotic drugs is faster in men than in women.11,13 On the other hand, women show greater improvement of psychotic symptoms due to slower metabolism of these drugs, but suffer more ADEs (e.g., weight gain, metabolic syndrome) associated with the drugs.21,25 Sex hormones decrease CYP1A2 activity during pregnancy and with oral contraceptive use.17,26 Therefore, dosage adjustment may be necessary when olanzapine or clozapine is prescribed during concomitant use of oral contraceptives or at pregnancy, depending on the specific drug and the patient’s conditions.
CYP2B6 expression and activity are higher in women than in men. Its activity also varies among different ethnic groups. In a previous study, CYP2B6 activity is lower in Hispanic men than in Caucasian or African-American men. In contrast, Hispanic women showed higher CYP2B6 activity when compared to Caucasian or African-American women. Therefore, drugs that are primarily metabolized by CYP2B6 may be less effective in women (especially Hispanic women) than in men.20
CYP2D6, which metabolizes >20% of prescribed drugs such as analgesics (e.g., codeine), antidepressants (e.g., selective serotonin reuptake inhibitors [SSRIs]), and haloperidol, exhibits extensive genetic poly-morphism.13,15,21 Ethnicity is a key factor for the genetic variation,21 and the prevalence of extensive metabolizers and poor metabolizers varies among different ethnic groups. Among the extensive metabolizers, CYP2D6 activity is higher in women than in men,21 and increased activity is seen during pregnancy.17,24
CYP3A4 is the most abundantly expressed CYP in the liver and is the predominant enzyme for phase I metabolism.11,27 Its expression (protein and mRNA) and activity are higher in women than in men. Drugs such as cyclosporine, erythromycin, nimodipine, and cortisol are substrates of CYP3A4, showing faster clearance among women.16,28 Although CYP3A4 is also responsible for about 60% of CYP-mediated metabolism of zolpidem, its overall clearance is actually slower in women than in men. Testosterone can stimulate the activity of CYP3A in metabolizing certain drugs and has been postulated to enhance zolpidem metabolism in men. In contrast, the lower testosterone level in women may cause a slower CYP3A4-mediated metabolism of zolpidem, resulting in a slower clearance and an increased risk of morning-after activity impairment.29,30
Phase II Enzymes: The major phase II enzymes are listed in TABLE 2. These particular enzymes are responsible for glucuronidation, sulfate-conjugation, N-acetylation, and methylation, respectively. Most phase II enzymes have a higher activity in men than in women.16 UGTs, the most predominant phase II enzymes in the liver, kidney, and intestine, are superfamily enzymes with two major subfamilies—UGT1 and UGT2.31 Both estrogens and androgens regulate the expression of the UGT2B subfamily of enzymes, and the activity of UGTs is increased during pregnancy.22,32,33
Men show a faster clearance of drugs that are primarily eliminated by glucuronidation. Thus, oxazepam, metabolized mainly by UGT2B15, has a longer half-life in women than in men.34,35
Glucuronidation is also a major metabolic pathway for antiretroviral drugs. Among HIV-infected patients, higher incidence of ADEs and possibly greater efficacy have been seen in women prescribed with antiretroviral drugs, and such a phenomenon may be attributed to a lower glucuronidation rate and slower clearance of these drugs in women than in men.36
Both glucuronidation and sulfate conjugation are the main pathways for eliminating acetaminophen. Women have slower clearance of acetaminophen than men, but the sex difference appears to be offset with the use of combined estrogen-progesterone oral contraceptives, which increase the activity of UGTs.37,38
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.27 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.39
The gastrointestinal (GI) transit rate can affect the plasma concentration and absorption of orally taken drugs.40 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.12,41 Captopril, felodipine, ampicillin, demeclocycline, and loratadine are some example drugs.12
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.36 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.42,43 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.44
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.12,21,27
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).45
Excretion: Both renal blood flow and glomerular filtration rate (GFR) are higher in men than in women.16 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.9,12,13,46
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.16 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.47 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).16 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.48,49 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.48,50-52
Furthermore, use of combined estrogen‑progesterone oral contraceptives can have profound effects on pharmacokinetics by reducing the plasma albumin level,27 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.7
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.53
Despite the differences in drug pharmacokinetics between men and women, sex-specific recommendations in dosage do not exist for most drugs. Pharmacists need to recognize the underrepresentation of women in clinical trials, and have the responsibility to inform consumers and emphasize to clinicians that women can differ significantly from men with respect to metabolism, absorption, distribution, and excretion of drugs. Pharmacists also need to be aware that pregnancy, oral contraceptive use, and hormonal replacement therapy can significantly change drug metabolism and drug clearance. If a woman consistently experiences more ADEs or less therapeutic effect from a particular drug, it may be necessary to discuss with her physician the possibility of changing the dosing regimen or switching to a different medication.
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