Gender Differences and Serum Drug Concentrations

Biological differences between men and women result in differences in response to drug therapy. Both pharmacokinetic and pharmacodynamic differences exist between men and women. In general, men have a larger body size than women, which results in larger distribution volumes and faster total clearance of many drugs in men compared with that in women. Moreover, greater body fat in women may lead to increases in distribution of lipophilic drugs in females (40). Slower gastric emptying of women can significantly delay the onset of effectiveness of enteric-coated dosage form as well as differences in gastric pH between men and women may also affect dissolution of a drug between genders (41). Hepatic metabolism of drugs by Phase I (oxidation, reduction, and hydrolysis through cytochrome P450's 1A, 2D6, and 2E1) and Phase II (conjugative metabolism by glucuronidation, glucuronyl transferase, methyltransferases, and dehydrogenases) mechanism and by combined oxidation/conjugative mechanism may result in faster drug clearance in men compared with that in women. However, metabolism of drugs by CYP2C9, CYP2C19, and N-acetyltransferase appears to be similar in both males and females. In contrast, metabolism of certain drugs that are substrates for CYP3A4 appeared to be mildly or moderately faster in women compared with that in men. Clearance of drugs that are substrates to P-glycoprotein appears to be comparable in both genders (40). Additional gender-related factors, such as intake of hormonal contraceptives, may also have further modulating effects on CYP2D6, CYP2C19 as well as phase II metabolism of drugs (42).

Women experience more adverse reactions to treatment with drugs than men. A Bayesian statistical analysis of sex difference in adverse drug reactions indicated that although about same numbers of adverse events were reported for both men and women, those reported for women were more serious. One example of a sex difference in toxicity of drugs is the drug-induced cardiac arrhythmia, torsades de pointe (43). The efficacy of antiretroviral therapy in HIV-infected patients appears to be similar between men and women, but women may experience higher toxicity profiles (44). Fleisch et al. recently commented that because of gender differences in pharmacokinetic and pharmacodynamic responses in drugs, more women should be recruited in clinical trials for new drugs. Traditionally, women are underrepresented as participants in clinical drug trials (45).

Theophylline is metabolized by CYP1A2. In one study involving 24 subjects, it was observed that theophylline metabolism is faster in women than in men (6 h in female non-smoker vs. 9.3 h in male non-smokers) (46). Phenytoin and naproxen are mainly metabolized by CYP2C9. Rugstad et al. (47) reported that there was an increase in plasma naproxen concentrations with age and that females also had higher plasma concentrations of naproxen compared with males. Although women showed slightly lower concentration of phenytoin compared with men when corrected for body weight and height, the difference was not statistically significant (48). The activity of CYP2C19 may be higher in males than in females. The metabolism of mephobarbital was significantly faster in males than in females when compared after a single oral dose of 400 mg of the drug. The sex difference was more significant with the R-enantiomer (49). Clomipramine, which is metabolized by CYP2D6 and CYP2C19, has a higher clearance rate in males compared with that in females (50).

Propranolol metabolism is also faster in males than in females (51). The metabolism of methylprednisolone is mediated by CYP3A4, and in one report, metabolism was higher in women than in men (52). Many other drugs are also metabolized by CYP3A4, the major isoenzyme of human cytochrome P450 enzyme system. Higher clearance of a drug that is a substrate of CYP3A4 in women has been reported. Wolbold et al. found twofold higher CYP3A4 levels in women compared with that in men based on their analysis of 94 well-characterized surgical liver samples. Higher expression in women was also observed in CYP3A4 messenger RNA (mRNA) transcripts, suggesting a pre-translational mechanism. Expression of pregnane X receptor (PXR), which plays a major role in induction of CYP3A4, was also correlated with CYP3A4 in mRNA level, but no sex difference was observed in the expression of PXR mRNA. No sex difference was also observed in P-glycoprotein expression (53). In contrast, Bebia et al. observed no sex difference in phenotype of CYP2C19, CYP3A4, and CYP2D6 based on a study of 161 normal subjects. CYP2E1 showed an age-associated increase, which developed earlier in male subjects than in female subjects (54). Many drugs are metabolized by conjugation. In one study, acetaminophen (paracetamol) clearance was 22% greater in young males compared with that in age-adjusted young females. This difference was entirely because of increase in activity of the glucuronidation pathway in males, and no sex difference was observed in other pathways of paracetamol metabolism (55).

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