Distribution

On average, women have a higher body fat percentage [the differences, however, decrease at older ages (72)], a smaller plasma volume, and a lower organ blood flow than men, with obvious implications for disparities in drug distribution. Moreover, the major protein groups responsible for binding in human plasma are influenced by sex hormone levels, so that plasma drug binding can clearly be influenced by gender. Note, however, that albumin is not greatly affected by gender (73). There were multiple reports of gender-related differences in aj-acid glycoprotein (AAG) concentrations (74-79), gender-dependent stereospecific binding (80,81), and estrogen-mediated decreases in AAG production (82). Nevertheless, gender differences in unbound fractions of disopyramide are lacking despite differing AAG levels (75). Further investigations did not demonstrate gender-related differences in free fractions of highly bound drugs in patients or in subjects receiving hormone replacement therapy or oral contraceptive pills (83,84).

During pregnancy, the effects on binding proteins are complex. As pregnancy progresses, the concentration of albumin, along with other plasma proteins, decreases (85). The effect of pregnancy on the AAG level is under debate: two studies report an overall decrease in AAG concentration over the course of pregnancy (86,87); other studies report no change (88), or decreases in AAG levels throughout pregnancy (85). Unresolved questions still exist regarding drug protein-binding capacity in the setting of pregnancy. Some researchers report that there is a steady increase in the production of endogenous ligands, such as free fatty acids, during pregnancy that compete for drug-binding sites distinct from their own albumin (89,90). Furthermore, protein-binding capacity may be reduced secondary to intrinsic alterations in protein structure during pregnancy (91). In addition, exogenous estrogens increase levels of the serum-binding globulins, which include sex-hormone binding globulins, corticosteroid-binding globulin, and thyroxine-binding globulin (92).

The differences in body fat may account for the increased distribution volumes for lipophilic drugs, such as benzodiazepines (93,94). A larger volume of distribution of diazepam has been observed in females versus males (95,96), with differences in both body fat proportion and gender-dependent changes in protein binding being cited for this disparity. This may lead to prolonged duration of effect due to increased half-life. Increased fat stores and differences in organ blood flow in women versus men have been implicated in the faster onset of action and prolonged duration of neuromuscular blockade in females with lipophilic paralyzing agents, such as vecuronium (97-101) and rocuronium (102).

The water-soluble compound, metronidazole, demonstrates a smaller volume of distribution in women versus men, although increased CL of metronidazole in females versus males accounts for a lower AUC for this drug in females (103). A smaller volume of distribution for the water-soluble fluoroqui-nolones in women versus men was observed (104,105). Both the oral CL and the volume of distribution of prednisolone are significantly higher in men compared with women (106).

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Do Not Panic

Do Not Panic

This guide Don't Panic has tips and additional information on what you should do when you are experiencing an anxiety or panic attack. With so much going on in the world today with taking care of your family, working full time, dealing with office politics and other things, you could experience a serious meltdown. All of these things could at one point cause you to stress out and snap.

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