Gender Differences in Pharmacological Response

Female sex has been shown to be a risk factor for clinically relevant adverse drug reactions. Is the increased risk due to sex differences in pharmacokinetics, in pharmacodynamics, or did females receive more medications and higher mg/kg doses than males? Recent studies suggest that all of the above may play a role. Generally, males weigh more than females, yet few drugs are dosed based on body weight. Drug concentrations are dependent on the volume of distribution (Vd) and clearance (Cl). Both parameters are dependent on body weight for most drugs independent of sex differences. Females have a higher percent body fat than males which can affect the Vd of certain drugs. Renal clearance of unchanged drug is decreased in females due to a lower glomerular filtration. Sex differences in activity of the cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes and renal excretion will result in differences in Cl. There is evidence for females having lower activity of CYP1A2, CYP2E1, and UGT; higher activity of CYP3A4, CYP2A6, and CYP2B6; and no differences in CPY2C9 and CYP2D6 activity. Pharmacodynamic changes can affect both the desired therapeutic effect of a drug as well as its adverse effect profile. The most widely reported sex difference is the higher risk in females for drug-induced long QT syndrome, with two-thirds of all cases of drug-induced torsades occurring in females. Females also have a higher incidence of drug-induced liver toxicity, gastrointestinal adverse events due to NSAIDs, and allergic skin rashes. In conclusion, at the minimum, it is important to take into account size and age as well as co-morbidities in determining the appropriate drug regiment for females, as well as males. There are still large gaps in our knowledge of sex differences in clinical pharmacology and significantly more research is needed.