1

GENDER DIFFERENCES IN CLINICAL RESEARCH

GAUTAM CHAUDHURI, M.D., Ph.D.CARLA JANZEN, M.D.

LAUREN NATHAN, M.D.BARBARA A. LEVEY, M.D.

DEPARTMENTS OF OBSTETRICS AND GYNECOLOGY

AND MOLECULAR AND MEDICAL PHARMACOLOGY

DAVID GEFFEN SCHOOL OF MEDICINE AT UCLA

2

DEFINITIONS

• SEX refers to the classification of living things, generally as male or female, according to their reproductive organs and functions assigned by chromosomal complement.

• GENDER refers to a person’s self-representation as male or female. Gender is rooted in biology and shaped by environment and experience.

3

SEX DIFFERENCES IN RECOVERY FROM STROKE

• Females are more likely than males to recover language ability after suffering a left hemisphere stroke

• Men and women differ in brain organization for language– Men rely on left inferior frontal gyrus to carry out

language tasks– Women use both the right and left inferior gyri to

carry out certain language tasks

4

SEX DIFFERENCES AND DEPRESSION

• Female gender is a major risk of depression by 2:1 ratio

• Prevalence of major depression in women (21.3%) versus men (12.7%)

5

WOMEN IN CLINICAL TRIALS

• FDA 1977 guidelines directed that women of child-bearing potential be excluded from Phase I and early Phase II trials but women could participate later.

• Child bearing potential was narrowly defined as any woman physiologically capable of becoming pregnant, regardless of sexual activity, sexual practices and contraceptive use

• In 1990, the NIH directed that women and minorities be included in clinical trials

6

SEX DIFFERENCES

• Physiological factors

• Molecular factors

7

SEX DIFFERENCES AND CLINICAL RESEARCH

• The following should be considered– Genetic differences– Phase of menstrual cycle– Premenopausal vs. postmenopausal– Use of oral contraceptives or hormone

replacement therapy– Pregnancy– Lactation

8

SEX DIFFERENCES

• Physiological factors– Generally lower

• Body weight• Organ size• Glomerular filtration rate

– Generally higher• Percentage of body fat

– Different gastric motility in women compared to men

9

GENETIC/MOLECULAR BASIS OF SEX BASED DIFFERENCES

• Genetic/molecular basis of sex-based differences may be due to:– Sexual genotype– Genes on sex chromosomes may be expressed

differently between males and females (single or double copies of the gene, differing meiotic effects, X chromosome inactivation, genetic imprinting)

– Source of X chromosome (maternal or paternal)

10

MOLECULAR FACTORS

• Men seem to have higher activity relative to women for:– Cytochrome P 450 (cyp) isoenzymes

• Cyp 1A2• Cyp 2E1

– Drug efflux transporter• P-glycoprotein• Some isoforms of glucuronyl transferase and sulfotransferases

• Women have higher– Cyp 2D6 activity– Cyp 3A4 activity

11

PRINCIPLES OF DRUG ACTION

• Absorption• Bioavailability• Volume of distribution• Plasma protein binding• Action on receptor site• Termination of activity

– Redistribution

– Metabolism

– Renal excretion

12

SEX DIFFERENCES AND ANTIDEPRESSANT PHARMACOKINETICS

• Oral contraceptives decrease the hepatic metabolism of imipramine because of changes in hepatic blood flow

• Imipramine dosage reduction is necessary in chronic long-term oral contraceptive users to 2/3rd that given to non-contraceptive users

• Women older than 50 years have higher plasma concentrations of amitriptyline than age matched men

13

BIOAVAILABILITY OF DRUGS

• Extent to which and the rate at which an administered drug dose reaches the systemic circulation unchanged

• Bioavailability of a drug administered intravenously is equal to unity

• Bioavailability of a compound administered as an oral, intramuscular, or subcutaneous formulation is assessed in relation to intravenous drug

14

HALF-LIFE OF A DRUG

volume of distribution Half-life = X log c2

clearance

15

DISTRIBUTION OF DRUGS

• Rate at which equilibrium between tissue and plasma concentration is achieved depends on:– Blood perfusion rate to organs– Drug lipid solubility– Drug’s ability to bind to proteins or tissues

16

LIPID SOLUBILITY AND DISTRIBUTION OF DRUGS

• If lipid soluble – more likely to cross biological barriers such as cell membranes, blood-brain barrier, and placenta

• If water soluble – will cross membranes only if it’s of small molecular size

17

DRUG METABOLISM

• Water soluble drugs– Eliminated unchanged after glomerular filtration

• Lipid-soluble drugs– Rendered more polar by metabolism prior to

excretion in bile or urine– Oxidation (hydroxylation, demethylation)– Conjugation (glucoronide, sulphate)

18

PHYSIOLOGICAL CHANGES IN PREGNANCY

• Total body water increases - up to 8 liters

• Plasma volume increases by 50%

• Plasma albumin falls by 5-10 g/L

• Increase in body fat by 3-4 kg

• Increase in body weight

• Maternal cardiac output increases by 30-50% during pregnancy (4.5 l/min 6 l/min)

19

EFFECTS OF INCREASE IN CARDIAC OUTPUT

•Uterine circulation 500 ml/min at term

•Effective renal plasma flow Increased by 75% over non-pregnant levels to 891 ml/min by 26 weeks (NP – 480 ml/min)

•Glomerular filtration rate Increased by 50% from 99 ml/min – non-pregnant to 152 ml/min – by 26 weeks

•Creatinine clearance rate 150-200 ml/min

20

INFLUENCE OF PHYSIOLOGICAL CHANGES IN PREGNANCY ON DRUG HANDLING

• Ingestion– Compliance

• Fear that fetus may be harmed• Nausea, vomiting and heartburn

• Absorption– Gastric function

• Delayed gastric emptying• Gastric acid secretion is decreased by 40%

– Functions of small intestine– GI transit is prolonged by 30-50%– Drugs if metabolized in gut wall eS chlorpromazine, may reduce

bioavailability• Epidural space

– Greatly increased vascularity in epidural space• Demerol more rapidly absorbed

21

CYTOCHROME P-450 AND SEX STEROIDS

• High levels of progesterone may inhibit some enzymes of P-450 system– CYP 1A2 leading to decreased elimination of

theophylline, caffeine, and zileuton

• High levels of progesterone may increase activity of some enzymes– CYP 3A4 and CYP 2C9 leading to increase in

hepatic elimination of drugs like phenytoin and sertraline

22

ANTICONVULSANTS AND PREGNANCY

• Phenytoin– Increased clearance resulting in lower serum

concentrations absorption

plasma protein binding metabolism

23

DRUG METABOLISM IN PREGNANCY

CARBAMAZEPINE PHENYTOIN

ARENE OXIDES (EPOXIDES)

PHENOLICCOMPOUNDS

HYDROLYZED

CONJUGATION WITH GLUCURONIC ACID

PHENOLICCOMPOUNDS

CONJUGATION WITH GLUCURONIC ACID

HYDROLYZED

OXIDATION OXIDATION

ARENE OXIDES (EPOXIDES)

24

ANTIBIOTIC LEVELS AFFECTED DURING PREGNANCY

• Ampicillin, penicillin, cefazolin levels decreased by 50%

• Gentamycin, tobramycin, and amikacin serum concentrations are also reduced

25

ASTHMA THERAPY AND PREGNANCY

– Inhaled steroids and beta agonists commonly used

– Theophylline serum concentrations can be elevated during pregnancy ( CYP 1A2)

26

CARDIOVASCULAR AGENTS AND PREGNANCY

• Serum concentrations of propranolol, labetalol, and atenolol not changed

• Lowered serum concentrations with metoprolol

27

SUBSTRATES - 11A2 2B6 2C19 2C9 2D6 2E1 3A4, 5, 7

amitriptylinecaffeineclomipramineclozapinecyclobenzaprine(Flexeril®)estradiolfluvoxaminehaloperidolimipramine N-DeMemexiletinenaproxen ondansetron phenacetin=>acetaminophen =>NAPQIpropranololriluzoleropivacainetacrinetheophyllineverapamil (R)warfarinzileutonzolmitriptan

bupropioncyclophosphamideifosfamide

Proton Pump Inhibitors:lansoprazoleomeprazolepantoprazoleE-3810Anti-epileptics:diazepam=>Norphenytoin(O)S-mephenytoinphenobarbitoneamitriptyline citalopramclomipramine cyclophosphamidehexobarbitalimipramine N-DeMEindomethacinR-mephobarbitalmoclobemide

NSAIDs:diclofenacibuprofenmeloxicamS-naproxen=>NorpiroxicamsuprofenOral Hypoglycemic Agents:tolbutamideglipizideAngiotensin II Blockers:losartanirbesartanamitriptylinecelecoxibfluoxetinefluvastatin glyburidephenytoin=>4-OH

Beta Blockers:carvedilolS-metoprololpropafenonetimololAntidepressants:amitriptyline clomipramine desipramineimipramine paroxetineAntipsychotics:haloperidolperphenazinerisperidone=>9OHthioridazinealprenololamphetaminebufuralolchlorpheniraminechlorpromazine

Anesthetics:enfluranehalothaneisofluranemethoxyfluranesevofluraneacetaminophen =>NAPQIanilinebenzenechlorzoxazoneethanolN,N-dimethyl formamidetheophylline=>8-OH

Macrolide antibiotics:clarithromycinerythromycin (not 3A5)NOT azithromycinAnti-arrhythmics:quinidine=>3-OH (not 3A5) Benzodiazepines:alprazolamdiazepam=>3OHmidazolamtriazolamImmune Modulators:cyclosporinetacrolimus (FK506)

28

SUBSTRATES - 21A2 2B6 2C19 2C9 2D6 2E1 3A4, 5, 7

nelfinavirnilutamideprimidoneprogesteroneproguanilpropranolol teniposideR-warfarin=>8-OH

rosiglitazonetamoxifentorsemideS-warfarin

codeine (=>O- desMe)debrisoquine dexfenfluraminedextromethorphanencainideflecainidefluoxetinefluvoxaminelidocaine metoclopramidemethoxyamphetaminemexiletinenortriptylineminaprineondansetronperhexilinephenacetinphenforminpropranolol (=>4OH)quanoxansparteinetamoxifentramadolvenlafaxine

HIV Antivirals:indinavirnelfinavirritonavirsaquinavirProkinetic:cisaprideAntihistamines:astemizolechlorpheniramineterfenidineCalcium Channel Blockers:amlodipinediltiazemfelodipinelercanidipinenifedipinenisoldipinenitrendipineverapamil

29

SUBSTRATES - 31A2 2B6 2C19 2C9 2D6 2E1 3A4, 5, 7

HMG CoA ReductaseInhibitors:atorvastatincerivastatinlovastatinNOT pravastatinsimvastatinSteroid 6beta-OH:estradiolhydrocortisoneprogesteronetestosteroneMiscellaneous:alfentanylbuspironecaffeine=>TMUcocainedapsone=>N-OH codeine- N- demethylationdextromethorphanfentanyl finasteridehaloperidol irinotecanLAAMlidocaine

30

SUBSTRATES - 41A2 2B6 2C19 2C9 2D6 2E1 3A4, 5, 7

methadoneodanestron pimozidepropranololquininesalmeterolsildenafilsirolimustamoxifentaxolterfenadinetrazodonevincristinezaleplonzolpidem

31

RECOMMENDATIONS

• Clarify use of terms sex and gender• Determine and disclose the sex of origin of

biological research materials• Identify endocrine status of research subjects• Design studies so that results can be analyzed by

sex• Promote research on sex at the cellular level• Encourage and support interdisciplinary research

on sex differences