GENDER DIFFERENCES IN CLINICAL RESEARCH

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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

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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 persons self-representation
  as male or female. Gender is rooted in biology
  and shaped by environment and experience.

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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

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SEX DIFFERENCES AND DEPRESSION

• Female gender is a major risk of depression by
  21 ratio
• Prevalence of major depression in women (21.3)
  versus men (12.7)

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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

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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

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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

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HALF-LIFE OF A DRUG

• volume of distribution
• Half-life X log c2
• clearance

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DISTRIBUTION OF DRUGS

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

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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
  its 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
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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
OXIDATION
PHENOLIC COMPOUNDS
ARENE OXIDES (EPOXIDES)
ARENE OXIDES (EPOXIDES)
PHENOLIC COMPOUNDS
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)

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CARDIOVASCULAR AGENTS AND PREGNANCY

• Serum concentrations of propranolol, labetalol,
  and atenolol not changed
• Lowered serum concentrations with metoprolol

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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