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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
1
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 selfrepresentation as male or female. Gender is
rooted in biology and shaped by environment
and experience.
2
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
3
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%)
4
WOMEN IN CLINICAL TRIALS
• FDA 1977 guidelines directed that women of childbearing 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
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SEX DIFFERENCES
• Physiological factors
• Molecular factors
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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
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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
8
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)
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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
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PRINCIPLES OF DRUG ACTION
•
•
•
•
•
•
Absorption
Bioavailability
Volume of distribution
Plasma protein binding
Action on receptor site
Termination of activity
– Redistribution
– Metabolism
– Renal excretion
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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
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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
13
HALF-LIFE OF A DRUG
volume of distribution
Half-life =
clearance
14
X log c2
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
15
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
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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)
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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)
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EFFECTS OF INCREASE IN
CARDIAC OUTPUT
•Uterine circulation
500 ml/min at term
•Effective renal plasma flow
Increased by 75% over nonpregnant 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
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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
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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
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ANTICONVULSANTS
AND PREGNANCY
• Phenytoin
– Increased clearance resulting in lower serum
concentrations
–  absorption
•  plasma protein binding
•  metabolism
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DRUG METABOLISM IN PREGNANCY
PHENYTOIN
CARBAMAZEPINE
OXIDATION
PHENOLIC
COMPOUNDS
OXIDATION
ARENE OXIDES
(EPOXIDES)
PHENOLIC
COMPOUNDS
ARENE OXIDES
(EPOXIDES)
HYDROLYZED
HYDROLYZED
CONJUGATION WITH
GLUCURONIC ACID
CONJUGATION WITH
GLUCURONIC ACID
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ANTIBIOTIC LEVELS AFFECTED
DURING PREGNANCY
• Ampicillin, penicillin, cefazolin levels
decreased by 50%
• Gentamycin, tobramycin, and amikacin
serum concentrations are also reduced
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ASTHMA THERAPY AND PREGNANCY
– Inhaled steroids and beta agonists commonly
used
– Theophylline serum concentrations can be
elevated during pregnancy ( CYP 1A2)
25
CARDIOVASCULAR AGENTS
AND PREGNANCY
• Serum concentrations of propranolol,
labetalol, and atenolol not changed
• Lowered serum concentrations with
metoprolol
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SUBSTRATES - 1
1A2
2B6
2C19
2C9
2D6
2E1
3A4, 5, 7
amitriptyline
caffeine
clomipramine
clozapine
cyclobenzaprine
(Flexeril®)
estradiol
fluvoxamine
haloperidol
imipramine NDeMe
mexiletine
naproxen
ondansetron
phenacetin=>
acetaminophen
=>NAPQI
propranolol
riluzole
ropivacaine
tacrine
theophylline
verapamil
(R)warfarin
zileuton
zolmitriptan
bupropion
cyclophosphamide
ifosfamide
Proton Pump
Inhibitors:
lansoprazole
omeprazole
pantoprazole
E-3810
Anti-epileptics:
diazepam=>Nor
phenytoin(O)
S-mephenytoin
phenobarbitone
amitriptyline
citalopram
clomipramine
cyclophosphamide
hexobarbital
imipramine N-DeME
indomethacin
R-mephobarbital
moclobemide
NSAIDs:
diclofenac
ibuprofen
meloxicam
S-naproxen=>Nor
piroxicam
suprofen
Oral Hypoglycemic
Agents:
tolbutamide
glipizide
Angiotensin II
Blockers:
losartan
irbesartan
amitriptyline
celecoxib
fluoxetine
fluvastatin glyburide
phenytoin=>4-OH
Beta Blockers:
carvedilol
S-metoprolol
propafenone
timolol
Antidepressants:
amitriptyline
clomipramine
desipramine
imipramine
paroxetine
Antipsychotics:
haloperidol
perphenazine
risperidone=>9OH
thioridazine
alprenolol
amphetamine
bufuralol
chlorpheniramine
chlorpromazine
Anesthetics:
enflurane
halothane
isoflurane
methoxyflurane
sevoflurane
acetaminophen
=>NAPQI
aniline
benzene
chlorzoxazone
ethanol
N,N-dimethyl
formamide
theophylline
=>8-OH
Macrolide antibiotics:
clarithromycin
erythromycin (not 3A5)
NOT azithromycin
Anti-arrhythmics:
quinidine=>3-OH (not
3A5)
Benzodiazepines:
alprazolam
diazepam=>3OH
midazolam
triazolam
Immune Modulators:
cyclosporine
tacrolimus (FK506)
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SUBSTRATES - 2
1A2
2B6
2C19
2C9
2D6
nelfinavir
nilutamide
primidone
progesterone
proguanil
propranolol
teniposide
R-warfarin=>8OH
rosiglitazone
tamoxifen
torsemide
S-warfarin
codeine (=>OdesMe)
debrisoquine
dexfenfluramine
dextromethorphan
encainide
flecainide
fluoxetine
fluvoxamine
lidocaine
metoclopramide
methoxyamphetamine
mexiletine
nortriptyline
minaprine
ondansetron
perhexiline
phenacetin
phenformin
propranolol (=>4OH)
quanoxan
sparteine
tamoxifen
tramadol
venlafaxine
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2E1
3A4, 5, 7
HIV Antivirals:
indinavir
nelfinavir
ritonavir
saquinavir
Prokinetic:
cisapride
Antihistamines:
astemizole
chlorpheniramine
terfenidine
Calcium Channel
Blockers:
amlodipine
diltiazem
felodipine
lercanidipine
nifedipine
nisoldipine
nitrendipine
verapamil
SUBSTRATES - 3
1A2
2B6
2C19
2C9
2D6
2E1
3A4, 5, 7
HMG CoA
Reductase
Inhibitors:
atorvastatin
cerivastatin
lovastatin
NOT pravastatin
simvastatin
Steroid 6beta-OH:
estradiol
hydrocortisone
progesterone
testosterone
Miscellaneous:
alfentanyl
buspirone
caffeine=>TMU
cocaine
dapsone=>N-OH
codeine- Ndemethylation
dextromethorphan
fentanyl finasteride
haloperidol
irinotecan
LAAM
lidocaine
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SUBSTRATES - 4
1A2
2B6
2C19
2C9
2D6
2E1
3A4, 5, 7
methadone
odanestron
pimozide
propranolol
quinine
salmeterol
sildenafil
sirolimus
tamoxifen
taxol
terfenadine
trazodone
vincristine
zaleplon
zolpidem
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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
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