Absorption

Factors that influence drug absorption are gastric emptying time, gastric and intestinal pH, and the gastrointestinal blood flow (45), along with the effects of presystemic hepatic and gut metabolism and transport. Metabolism and active transport back into the lumen can also affect systemic bioavailability. Characteristics of stomach and proximal jejunal fluids, including pH, osmolality, electrolyte concentrations, and levels of bile acids and proteins, do not seem to vary significantly by gender (46-49), although it has been reported (50) that mean basal acid outputs were significantly higher for male patients than for female

Table 1 Gender Differences in PK Parameters

PK process

Components

Gender-based differences

Bioavailability

Distribution

Metabolism

Gastrointestinal tract physiology

Extrusion by drug transporters, such as intestinal Pgp Gut enzymes, such as alcohol dehydrogenase and intestinal CYP3A4

Body composition: body size, percent body fat, plasma volume, and organ blood flow

Protein binding: extent of tissue and protein binding of the drug

Hepatic enzymes: Phase I metabolism reactions in the liver (oxidation, reduction, and hydrolysis mediated through the cytochrome P450 system)

Gastric emptying time is slower in females than males, mainly secondary to the effects of estrogens Intestinal Pgp levels do not seem to consistently vary by gender

Gastric levels of alcohol dehydrogenase are higher in males than females; intestinal CYP3A4 levels do not consistently vary with gender Women have lower body size than men; women have a higher proportion of body fat than men; plasma volume is greater in men than women, although volume varies throughout the menstrual cycle and during pregnancy; organ blood flow is greater in women than men Albumin concentrations do not seem to consistently vary with gender, but endogenous estrogens decrease the levels of AAG in the plasma, so women have lower concentrations of AAG than men. Exogenous estrogens increase levels of the serum-binding globulins (such as sex-hormone binding globulins, corticosteroid-binding globulin, and thyroxine-binding globulin) Data on varying levels of CYP expression and activity using in vitro systems exist, but the majority of studies that examine CYP (mainly CYP3A4) substrates for differences in PK parameters in men and women are inconsistent; general trend toward higher rates of metabolism for CYP3A4 substrates in women versus men

(Continued )

Table 1 Gender Differences in PK Parameters (Continued)

PK process

Components

Gender-based differences

Excretion

Hepatic transporters: hepatic Pgp or MDR1

Renal clearance: renal excretion is dependent on filtration, secretion, and reabsorption

Men seem to have higher hepatic Pgp levels than women, with higher drug clearances in women versus men for drugs that are substrates of Pgp Renal clearance of drugs that are not actively secreted or reabsorbed is dependent on GFR, which is directly proportional to weight; gender differences for these drugs are attributable to weight differences. Drugs that are actively secreted by the kidney may show gender differences in excretion

Source: From Refs. 42, 171.

Abbreviations: PK, pharmacokinetics; AAG, a1-acid glycoprotein.

patients with gastroesophageal reflux disease, gastric ulcer, and duodenal ulcer. Gastrointestinal motility is influenced by sex hormones (51,52), implying that gender-based disparity in motility may exist and that the transit time in women may vary throughout pregnancy and the menstrual cycle. Estrogen and its equivalents may inhibit gastric emptying (53,54), whereas the effects of progesterone depends on its concentration (55,56). Gastric transit time has been demonstrated by many researchers to be slower in females than males (57-61).

At least some drug-metabolizing enzymes located in the intestine also vary by gender (57,62,63). However, significant differences in gut expression of CYP3A isozymes in enterocytes between males and females have not been consistently observed (64,65). Potential gender differences in Pgp activity in the gut have been hypothesized based on the reports on differences in hepatic content (66). The data using oral fexofenadine as a probe of Pgp in humans, however, failed to find any gender differences in plasma concentration-time profiles of fexofenadine (67).

Several clinical PK studies reveal differences in bioavailability for certain drugs based on gender. A population PK analysis of mizolastine, an orally administered antihistamine, demonstrated a slower absorption of this drug in men versus women, contributing to variability in drug concentrations by gender (68). Two studies have demonstrated an increased absorption rate for some salicylate formulations in females compared with males (69,70), though other authors failed to show this difference (71).

In summary, while gastrointestinal motility and enzyme activity vary by gender, studies published thus far have not consistently shown a gender impact on drug bioavailability. Furthermore, studies that examine differences in bioavailability are few and confounded by variability in other PK processes, such as distribution, metabolism, and excretion. The present evidence, however, suggests that gender-based differences in bioavailability are not of great clinical significance.

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