Sex Differences in Drug Disposition

Table 4

Some drugs that display sex differences in pharmacokinetics.*

Drug	Pharmacokinetic parameter	Comments
Acebutolol [76]	Area under the concentration-time curve	The concentration-time profile is larger in women, suggesting greater therapeutic and potential side effects
Aspirin [36]	Clearance, half-life	Aspirin is cleared more rapidly from women
Benzylamine		Following transdermal absorption, women excrete 3 times more than men
Beta-Blockers; Atenolol [77]	Oral clearance lower in women, lower volume of distribution in women resulting in higher systemic exposure	The greater reduction in blood pressure in women was due to pharmacokinetic and not pharmacodynamic differences
Cefotaxime [79]	Clearance	Clearance is decreased in women
Ciprofloxacin [80]	Clearance	Clearance is lower in women
Cephradine [81]		Slower rate of absorption and lower bioavailability in the female; increased clearance and decreased terminal elimination half-life in pregnancy
Clozapine [82]		significantly higher plasma levels for women
Diazepam [83]	Plasma binding	Larger volume of distribution in women
Ethanol [86]	Volume of distribution, clearance, and first-pass metabolism	When ethanol is ingested, men metabolize more in first pass metabolism; in addition the volume of distribution is smaller in women
Ferrous Sulfate	Absorption	Absorption higher in prepubertal girls than boys
Fluoroquinolones [87]	Volume of distribution	Lower in women
Gemcitabine [79]	Clearance	Clearance is lower in women
Heparin [79]	Clearance	Clearance is lower in women
Iron [79]	Absorption measured as % of the dose incorporated into red blood cells	More ingested iron is absorbed by women than men
Methylprednisolone [90]	Plasma binding, clearance, volume of distribution, and half-life	Plasma binding and 𝑉𝑑 are similar in men and women; CL is increased in women and as a consequence, half-life is shorter
Metronidazole	Volume of distribution	Smaller volume of distribution and increased clearance resulting in lower AUC in women
Metoprolol [100]	Plasma binding, clearance, volume of distribution, half-life	Clearance increases during pregnancy, but is smaller in women; 𝑉𝑑 smaller in women than men, but increases during pregnancy; plasma binding is unaffected by sex or pregnancy
Midazolam [101]	Considered to be probe for CYP3A4, not substrate for PGP	No sex difference in clearance following either oral or intramuscular administration; interpretation complicated by differences in intestinal and hepatic CYP3A4 levels
Mizolastin [102]	Oral availability	Longer duration for absorption in men, contributing to variability in drug concentrations in men and women
Naratriptan [79]	Oral availability, peak concentration	Oral bioavailability being greater in women results in peak concentration is higher in women than men
Ofloxacin	Clearance	Clearance is lower in women
Olanzapine [103]	Higher activity in women for CYP3A4 and CYP2D6	Significantly higher plasma levels for women
Ondansetron [79]	Oral availability, clearance	Oral availability is increased in women
Phenytoin [104]	Plasma binding	Plasma binding decreases during pregnancy; however, the intrinsic clearance is unchanged so the free concentration is unchanged
Prednisolone [105]	Distribution	Oral clearance and volume of distribution significantly higher in men
Propranolol [106]	Plasma binding, clearance, volume of distribution, and half-life	Plasma binding is similar among men and women; however, plasma binding increases during pregnancy. Clearance is smaller in women. 𝑉𝑑 is similar in both men and women and does not appear to be altered during pregnancy. Half-life is decreased in women compared to men but does not appear to be altered during pregnancy
Quinine [79]	Plasma binding, clearance, volume of distribution, and half-life	Plasma binding is unaltered during pregnancy, as is clearance.; 𝑉𝑑 decreases during pregnancy, as does half-life
Rifampicin [9]	Women absorb the drug more efficiently	—
Rizatriptan [79]	Urinary excretion, clearance, volume of distribution, half-life	Urinary excretion is similar in men and women; clearance is greater in men
Rocuronium	Distribution	Prolonged drug duration due to higher fat content and lower organ blood flow in women
Salicylate [108]	Absorption	Increased rates of absorption in women
Selective Serotonin; Reuptake; Inhibitors [91]	Plasma concentrations are higher in women	Decreased metabolism by hepatic CYP
Vecuronium	Distribution	Prolonged drug duration due to higher fat content and lower organ blood flow in women
Verapamil; Calcium channel blocker [94, 95]	Clearance following intravenous administration more rapid in women, but oral clearance higher in men than women. Substrate for both CYP3A4 and PGP	Sex differences in hepatic and gut CYP3A4 and PGP lead to complex differences in clearance between men and women. Bioavailability from the gut is greater in women. The greater bioavailability leads to increased systemic exposure in women
	Oral clearance is lower in women

*Pregnancy-related PK changes are in italics font.
Table modified from Soldin and Mattison [5].