Download Female sex has been shown to be a risk factor for clinically relevant

Supplemental Table 1. Gender differences in absorption, distribution, metabolism, and excretion
Parameter
Drug bioavailability1-12
Absorption
Gastric acid secretion
Gastric emptying
Gastrointestinal transit times
Gut metabolism
Body composition1-14
Body surface area
Organ (heart) size
Organ blood flow
Total body water
Plasma volume
Body fat content
Cardiac output
Pulmonary function
Drug distribution1-14
Volume of distribution
Plasma protein binding to
- Albumin7,8,15,16
- 1-acid glycoprotein16,17
- Globulins18
Sex differences
M>W
M > W > P1-3. Decreases absorption of weak acids but
increases absorption of weak bases in M
M > W > P3-9. E inhibit gastric empting7
M=W
M > P > W. Absorption increases when body surface are
is larger
M > W. Greater blood flow to skeletal muscle and liver in
M; greater to adipose tissue in W.
Blood flow increases during P
M>P>W
P > M > W. Varies during the menstrual cycle and .
W>M
M > P > W. Increase rate of distribution in M
M > P > W. Increase pulmonary elimination in M
W > M. Higher Vd for lipophilic drugs in W
M > W. Higher Vd of hydrophilic drugs in M
M = W. P and OC reduce plasma albumin and increases
free drug plasma levels.
M > W. E, OC and P decrease its plasma levels
E increase sex-hormone binding, corticosteroid-binding
and thyroxine-binding globulin.
Parameter
Drug transporters
Hepatic P-glycoprotein
OCT2
OATP1B1-3
1
Sex differences
M > W10,19,20
M > W21,22. E downregulates OTC2
M > W21
Drug metabolizing enzymes and transporters
Phase I metabolic reactions
CYP1A2: M > W23-27. Decreases in pregnancy and by
(hydrolysis, oxidation, reduction)
OCP
mediated via cytochrome P450 (CYP) CYP2B6: W > M27
isoforms
CYP2C9: M = W21,27,28
CYP2C19: M = W29
Decreases in pregnancy and by OCP30,31
CYP3A4: W > M27,32,33. Increases by OCP
CYP2D6: M > W23,31,34. E induces35-37 and OCP
decreases CYP2D6 activity31
CYP2E1: M > W38. Increases by OCP
Phase II metabolism
- Uridine diphosphate
- M > W. Increase by OCP and E and during
gluronosyltransferases (UGTs 1/ 2)
pregnancy28,37,39
- N-Acetyltransferases (NAT)
- M = W24
- M > W40
- Catechol-O-methyltransferase
- Acetyl-/Butiryl-cholinesterase
- M > W41
- Xantine-oxidase
- F > M24,25
- Gastric alcohol dehydrogenase
- M > F. Higher alcohol plasma levels in W42,43
Drug excretion12,44,45
- Renal blood flow
M > W. Renal Cl increases during P
- Glomerular filtration rate
Drugs actively secreted by the kidney may show sex
- Tubular secretion/ reabsorption
differences in renal excretion
Cl: clearance. E: estrogens. GFR: glomerular filtration rate. GI: gastrointestinal. M: men. OCP: oral contraceptives. P: pregnancy. P-gp: P-glycoprotein. Vd:
volume of distribution. W: women.
2
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5
Supplemental Table 2. Sex-related differences in drug pharmacokinetic parameters
Drug class
Outcomes in females
Anesthetics: Propofol
Alcohol
Plasma propofol levels decline more rapidly in W at the end of infusion1-5.
Lower gastric alcohol dehydrogenase activity in W. Higher plasma
concentrations in W as compared to M following an equivalent drink6.
Antidepressants
Higher AUC and Cmax in W7.
H1-Antihistamines
Slower metabolism and elimination in W8,9.
Antipsychotic drugs (1) Higher plasma levels and Vd and lower Cl in W10-12. Reduce the dosage in F
or increase dosage in M. Olanzapine is more rapidly eliminated in M than in
W13.
Aspirin
Higher bioavailability and plasma levels of aspirin and salicylate are higher in
W possibly due to lower activity of aspirin esterase, larger Vd and lower Cl in
W than in M14-16. Differences disappear with OCP14.
Benzodiazepines
Lower initial plasma levels due to larger Vd, and possibly higher Cl, in W17-21.
OC reduce their Cl. Higher plasma levels of free diazepam in W21.
Beta-receptor agonists W are less sensitive4.
Beta blockers:
W have higher plasma levels due to a smaller Vd and slower Cl22-24. Drug
Metoprolol, propranolol exposure to metoprolol increases by OC25.
Renal Cl of atenolol and metoprolol increases during P due to enhanced
hepatic metabolism26,27.
Calcium channel
Faster Cl of verapamil28, and nifedipine29 in W. Increased bioavailability and
blockers
decreased clearance of oral verapamil in W compared to M30,31.
Digoxin
W have higher serum digoxin concentrations due to reduced Vd and lower
Cl32,33. Drug Cl increases during P34.
Glucocorticoids
Oral Cl and Vd of prednisolone are higher M. Prednisolone clearance was
reduced by OC35-37.
Heparin
W had higher plasma levels and APTT values than M due to a lower Cl8,38-40.
Iron
Oral absorption of iron is greater in W than in M41.
Isosorbide Mononitrate W had significantly higher serum plasma concentrations compared to men,
probably due to the lower body weights in females42 .
Labetalol
Labetalol concentrations are 80% higher in W43.
Lidocaine
W has a larger Vd and may require a higher i.v. bolus dose than M. Higher
free plasma levels in W receiving OCP, as alpha 1-acid glycoprotein levels
are reduced by oestrogens21.
Slower onset and offset of action in W2,4,44.
-opioid (OP3)
receptor agonists (2)
Neuromuscular
Lower Vd, higher plasma levels, faster onset and prolonged duration in W
blocking drugs (3)
due to the higher body fat and lower Vd4,45-50.
Paracetamol
Lower plasma levels and higher Cl in M due to increased activity of the
glucuronidation pathway51,52. OCP increase drug clearance52.
Procainamide
Plasma levels are higher (30%) in W due to a lower BMI and Vd53.
Quinidine
Plasma protein binding decreases during P54.
Selective serotonin
W present higher plasma levels, probably related to sex-related activity of
reuptake inhibitors (4) various CYP enzymes7,55-57.
Statins
Higher plasma levels of lovastatin and simvastattin in W58.
Theophylline
Metabolism is faster and half-life is shorter in W than in M59. Plasma protein
binding decreases and the Vd increases during P.
Torasemide
Higher Cmax and lower Cl in W than in M60,61.
6
Tricyclic
antidepressants
Verapamil
Vorapaxar
Warfarin
Zolpidem
Free plasma concentrations of imipramine, clomipramine and nortriptyñine
are higher in W and in pregnant women7,62.
Faster Cl in i.v. W probably due to the higher activity of CYP3A4 or lower
activity of P-gp; lower Cl in W after oral administration28,30,63.
The Cmax and AUC were 30% higher in women but no dose adjustement is
required64.
Higher free plasma levels in W8,65.
Plasma levels and AUC are higher, and clearance is lower in W66
Abbreviations: AUC: area under the curve. BMI: body mass index. Cl: clearance. Cmax: peak plasma drug
concentrations. CYP: cytochrome P450 isoforms. i.v.: intravenous. M: men. OC: oral contraceptives. P: pregnancy.
P-gp: P-glycoprotein. Vd: volume of distribution. W: women.
(1): olanzapine, clozapine, pimozide, haloperidol.
(2): fentanyl, morphine, pentazocine, ramifentanil.
(3): atracurium, pancuronium, rocuronium vecuronium.
(4): citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline
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10
Supplemental Table 3. Sex differences in drug pharmacodynamics
Drug class
Alcohol
Anesthetics: Propofol
ACEIs
Antidepressants
Antipsychotic drugs:
Aspirin
Benzodiazepines
Beta-blockers
Digoxin
Glucocortioids
Outcomes
Higher vulnerability of W to acute and chronic complications of alcoholism1
W are less sensitive to propofol2. W wake up faster and require higher doses
than M for the same effect2-6
No mortality benefit in W with asymptomatic LV systolic dysfunction7
W respond better to selective serotonin/noradrenaline uptake inhibitors. M respond
better to TCA and MAO inhibitors than W8-15
More effective in W. They require lower doses to control symptoms16-18
It has a better protective effect against stroke in W and against MI in M19. Aspirin is
more active in vitro in male platelets20,21. Aspirin resistance is more frequent in W22
Diazepam impairs psychomotor skills to a greater extent in W. They should be
initiated at lower dosages in W23
Greater reduction in blood pressure and heart rate in W treated with metoprolol
and propranolol24
W with HF have an increased risk of mortality on digoxin therapy. W require lower
doses and lower plasma levels (< 0.8 ng/ml)25-27
Females are more sensitive to the effects of methylprednisolone on cortisol
suppression28
Heparin
Ibuprofen
Lidocaine
-opioid (OP3) and *
(OP2) receptor agonists
(1)
Neuromuscular blocking
drugs (2)
Paracetamol
rt-PA
SSRIs (3)
Verapamil
Warfarin
Zolpidem
W had increased partial thromboplastin time, even after weight-adjusted dosing,
suggesting an increased sensitivity29
Less effective in W30
W may require a higher i.v. bolus doses to achieve the same plasma
concentration31
W experience more pain and are more sensitive to morphine and  receptor
agonists2,32-37. M require 30-60% greater dose of morphine and  receptor agonists
for the same pain relief23,33-35,38
W are more sensitive and require lower (20-30%) doses than M due to a smaller
Vd2,39-44. If a rapid onset of action is required the dose should be increased in M
W displayed lower Cl and Vd compared to M45. Oral contraceptives increase drug
clearance18,46
W with acute ischemic stroke obtein more benefit from rtPA than M47-51
W respond better than M, being the preferred therapy8-10,15
Greater reduction in blood pressure and heart rate in W52
W need less warfarin per week than M53,54. Doses should be modified to reduce
the risk of excessive anticoagulation in F
The recommended initial dose is lower in W55
Abbreviations: ACEIs: angiotensin-converting enzyme inhibitors. E: estrogens. HF: heart failure. M: men. MI:
myocardial infartion. OCP: oral contraceptives. rt-PA: recombinant tissue plasminogen activator. SSRIs SSRIs:
selective serotonin reuptake inhibitors.
(1) alfentanyl, butorphanol*, fentanyl, morphine, nalbuphine* pentazocine*, remifentanyl.
(2) atracurium, pancuronium, rocuronium and vecuronium.
(3): citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline
11
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14
Supplemental Table 4. Examples of sex differences in adverse drug reactions (ADRs)
Drug class
Analgesic drugs
Anaphylactic shock
Anesthetic drugs
Angiotensin converting
enzyme inhbitors
Anorectics
Antiarrhythnmic drugs
Anticoagulants:
H1-Antihistamines
Antiplatelets
Antipsychotics
Aspirin
Beta blockers
Benzodiazepines
Calcium channel
blockers
Digoxin
Diuretics
Drug-induced TdP
GPIIb/IIIa inhibitors
Heparins
Opioid receptor
agonists
NSAIDs
Paracetamol
Procainamide
Skin diseases
Statins
Thiazides
Thiazolidinediones
Thrombolytics
Unfractioned heparin
Zolpidem
Outcomes in females
W report more adverse effects to perioperative analgesic drugs1.
Anaphylactic shock induced by neuromuscular blocking agents, hypnotics,
opioids and benzodiazepines is more frequent in W2.
W are more prone to ADR postoperatively2-4
Dry cough is 2-3 times more frequent in W5-7. No gender preference for
angioedema/urticaria8.
Cardiac valvulopathy is more frequent in W exposed to phentermine,
dexfenfluramine or fenfluramine9.
Higher risk of QT prolongation and TdP in W10.
More frequent and severe bleedings in W11-19
W are more vulnerable to sedation and drowsiness20-22
More frequent and severe bleedings in W23
W present more extrapyramidal and anticholinergic effects and QTc
prolongation. M reported more sexual problems24-27
Increased risk of bleeding in W28. More ulcer complications in M29
Enhanced BP lowering and heart rate reduction with metoprolol in W30.
Diazepam impaired the psychomotor skills more in W than in M31.
Dependency is more frequent in W26
Higher risk of edema in W32. Women taking OCP and diazepam during
menstruation become relatively intoxicated33
Higher mortality in F with heart failure34. Digoxin plasma levels < 0.8 ng/mL
are recommended in W35
Higher rates of hospitalizations due to hypo-osmolarity, hypokalemia and
hyponatremia and higher risk of arrhythmias in W15,35-39
W have a longer QTc intervals and devep TdP more frequently than M40-44
W experience more bleeding than M23,45
W present higher bleeding risk12,46,47
W experience more ADRs (nausea and vomiting, respiratory depression)
despite smaller dose requirements for pain control48-52
M display a higher prevalence of ADRs than W29,53-55
Acute liver failure die to paracetamol overdose is more common in W56
Systemic lupus erythematosus more common in W57,58
W > M (systemic lupus erythematosus and photosensitivity57,59
Myopathy is more frequent in older W with low body weight60,61
More hyponatremia and hypokalemia in W62
Double the risk of fractures among diabetic F, but not among M63-66
Higher risk of bleeding67-69 and intracranial hemorrhagic in W70,71
W develop higher plasma levels and higher bleeding risk12,19
To reduce the risk of morning-after activity impairment decrease the dose of
zolpidem by 50% in W72
Abbreviations: ACEIs: angiotensin-converting enzyme inhibitors. E: estrogens. HF: heart failure. 5-HTTT: serotonin
transporter. ADR: adverse drug reactions. BP: blood pressure. CV: cardiovascular. GP: glycoprotein.
NSAID: non-steroidal anti-inflammatory drugs. OC: oral contraceptives. QTc: corrected QT interval. TdP:
torsades de pointes. W: women.
15
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