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Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, New York
Abstract I. Introduction II. Membrane Transport in Tissues A. Kidney 1. Anions. 2. Cations. B. Liver 1. Anions. 2. Cations. C. Intestine D. Brain E. Other Tissues III. Conclusions
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I. Introduction |
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; Fletcher et al., 1994; Harris et al., 1995). The increased bioavailability of ethanol after oral administration has been reported in women as a result of higher alcohol absorption due to lower gastric alcohol dehydrogenase activity (Fletcher et al., 1994; Harris et al., 1995), and aspirin is absorbed more slowly in men than in women after oral dosing (Harris et al., 1995). The effect of gender on hepatic metabolism has been extensively examined for a number of drugs (Bonate, 1991; Fletcher et al., 1994; Harris et al., 1995). The enzyme, cytochrome P-450 3A4 (CYP 3A4) is involved in the metabolism of over 50% of drugs in clinical use including erythromycin, lidocaine, and midazolam and is also responsible for the hydroxylation of steroid hormones. The activity of CYP 3A4 in women is 1.4 times greater than that in men (Harris et al., 1995; Gleiter and Gundert-Remy, 1996). Conjugation reactions also demonstrate gender-related differences. The glucuronidation of diflunisal and paracetamol is higher in men than in women due to higher glucuronosyl transferase activity in men, with no sex-associated differences in sulfation (Gleiter and Gundert-Remy, 1996). Gender-based differences in protein binding have been observed for diazepam, chlordiazepoxide, and imipramine, with nonpregnant women having higher unbound fractions of these drugs compared with men (Harris et al., 1995; Kashuba and Nafziger, 1998). This may be due to the slightly lower concentrations of 
-1-acid glycoprotein and lipoprotein reported in women; the plasma concentration of -1-acid glycoprotein is decreased by estrogen (Beierle et al., 1999). Gender-related differences in drug response have not been extensively studied; however, a gender effect in pharmacodynamics has been well described for psychotropic drugs. The greater improvement and more severe adverse effects in response to antipsychotic drugs such as chlorpromazine and fluspirilene have been reported in women, at least in part, due to differences in estrogen concentrations; estrogen has been shown to act as a dopamine antagonist (Fletcher et al., 1994; Harris et al., 1995). As well, Kaasinen et al. (2001) have reported that women have significantly higher dopamine D2-like receptor binding than men in the frontal cortex, which may contribute to gender-related differences in the incidence, clinical course, or treatment response in neuropsychiatric diseases that are associated with dopaminergic neurotransmission. There is a gender difference in the response to the cholinesterase inhibitors, rivastigmine and physostigmine, in that female rats exhibit a greater inhibition of cholinesterase in the cerebral cortex, hippocampus, and striatum compared with male rats: orchidectomy completely abolished the difference suggesting that a testicular hormone may be suppressing the effect of the cholinesterase inhibitor by affecting its brain uptake or its interaction with cholinesterase (Wang et al., 2000). Women on hemodialysis exhibit lower responses to recombinant erythropoietin than male patients (Ifudu et al., 2001). It is not known if these differences are due to inherent biological differences in response to erythropoietin or due to other factors including differences in endogenous erythropoietin levels (Ifudu et al., 2001). More adverse effects for antihypertensive drugs are reported in women than in men (Harris et al., 1995). The gender-related differences in pharmacokinetics and pharmacodynamics may explain, at least in part, the interindividual variations observed in drug disposition, therapeutic response, and drug toxicity and are of particular concern for those drugs with relatively narrow therapeutic ranges (Harris et al., 1995; Gleiter and Gundert-Remy, 1996).
Facilitated transport systems in the intestine, liver, and kidney have been known to play important roles in the absorption and elimination of a variety of clinically significant drugs (Zhang et al., 1998). Drugs must traverse across biological membranes via simple diffusion or physiological transporters to produce therapeutic efficacy (Levy, 1998). Gender-associated differences in transport processes for endogenous and exogenous substrates have been reported in various organs of the body, including kidney, liver, intestine, and brain, for rats, mice, and humans (Kleinman et al., 1966; Orzes et al., 1985; Anton et al., 1986; Morissette et al., 1990; Uhland-Smith and DeLuca, 1993; Sibug et al., 1996). Table 1 summarizes the gender-associated differences in transport activities in humans, evaluated predominantly in clearance studies, whereas Table 2 summarizes the literature information regarding gender differences in transporter mRNA and/or protein expression in tissues. This review will focus on recent knowledge of gender-associated differences in the transport of endogenous compounds and xenobiotics in a variety of body organs and will discuss the implications and the clinical significance of these findings.
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II. Membrane Transport in Tissues |
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There are gender differences in renal handling of both organic and inorganic anions and cations.
1. Anions.
The renal clearance of p-aminohippurate (PAH1) is decreased in female rats due to decreases in both the filtered and secreted amounts. In females, the maximal uptake (Vmax) into kidney basolateral membrane vesicles is decreased by 52 ± 9% (p < 0.05), and the Michaelis-Menten constant (Km) for uptake into kidney brush-border membrane vesicles is increased by 163 ± 8% (p < 0.05), compared with male rats (Cerrutti et al., 2001). Similar results have been noted in older studies using kidney slices. The transport rate of PAH by kidney slices isolated from male rats is higher than that in female rats with higher Vmax values compared with female rats (Kleinman et al., 1966; Bowman and Hook, 1972) (Table 3). The rate of accumulation of PAH in renal cortical slices of adult male rats is decreased by castration or by blockade of testosterone receptor sites whereas ovariectomy does not increase the transport of PAH in mature female rats. Furthermore, treatment with estradiol in male rats does not reduce renal tubular transport of PAH whereas chronic (repeated) treatment with testosterone stimulates PAH transport in males more than in females. These results indicate the important role of sex hormones in the renal tubular transport of PAH and suggest distinct renal effects of testosterone compared with estradiol (Braunlich et al., 1993). Similar effects have been reported for the renal tubular transport of Diodrast, amino acids, and thiosulfate (as reviewed by Kleinman et al., 1966).
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The urinary excretion of zenarestat, an aldose reductase inhibitor, shows remarkable gender differences in rats and mice (Tanaka et al., 1991, 1992), whereas there is no significant difference between male and female dogs and humans (Tanaka et al., 1992) (Table 4). The ratios of the renal clearance of zenarestat to clearance of zenarestat by glomerular filtration are less than one in male rats and substantially greater than one in female rats. After pretreatment of rats and mice with probenecid, an inhibitor of the active secretion of many organic anions, a marked reduction in the urinary excretion of zenarestat is observed in females but not in males. These results suggest that zenarestat is, at least in part, actively secreted in the kidneys of female rats and mice and active renal tubular secretion of this compound is lacking, or negligible, in male rats and mice (Tanaka et al., 1991, 1992). In addition, the urinary excretion of zenarestat is decreased in female rats with experimentally induced chronic diabetes mellitus due to a decrease in active secretion, whereas there is an increase in the urinary excretion of the drug in male rats with experimentally induced acute or chronic diabetes, most likely due to a reduction in testosterone levels in diabetic states (Tanaka et al., 1993). Similarly, it has also been reported that there are gender differences in the renal excretion of perfluorooctanoic acid (Hanhijarvi et al., 1982), S-pentachlorophenyl-N-acetyl-L-cysteine (Smith and Francis, 1983), carnitine (Carter and Stratman, 1982), nilvadipine metabolite (M3) (Terashita et al., 1995) and 1-aminocyclohexanecarboxylic acid (Anton et al., 1986). These compounds are rapidly excreted by an active renal secretion in female rats whereas this secretory mechanism appears to be absent or relatively inactive in male rats (Carter and Stratman, 1982; Hanhijarvi et al., 1982; Smith and Francis, 1983; Anton et al., 1986; Terashita et al., 1995).
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Egualen sodium, an antiulcer drug, demonstrates a marked sex-related difference in the urinary excretion of unchanged drug and metabolites in rats. The renal clearance of unchanged drug in male rats is 21 times lower than that in female rats, and the urinary excretion of egualen represented 2.1 and 39.5% of the dose in male and female rats, respectively (Sato et al., 2000) (Table 5). Egualen is secreted in the renal tubules by a probenecid-inhibitable process, which can be inhibited by testosterone. Gonadectomized male rats have a similar renal clearance of egualen as female rats, and treatment of gonadectomized rats with testosterone decreased the renal clearance of egualen (Sato et al., 2000) (Table 6).
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Sodium/sulfate cotransport in kidney cortex brush-border (BBM) vesicles and sulfate/anion exchange in basolateral (BLM) vesicles, isolated from female and male guinea pig kidneys, have been studied (Lee et al., 1999a). No statistically significant differences in Km and Vmax for uptake were found, although uptake values for female animals tended to be greater; the lack of significance may reflect the small number of animals studied (n = 4). Sodium/sulfate cotransport is increased in renal epithelial cells in the presence of estrogen (Lee et al., 1999b). Postmenopausal women demonstrate a decreased renal reabsorption of sulfate compared with premenopausal women, although this was not reversed by estrogen supplementation (Benincosa et al., 1995).
A significant gender-related difference occurs in the renal reabsorption of urate in humans, which is of clinical significance. A significant decrease in tubular urate postsecretory reabsorption in the kidneys of adult women leads to a greater urinary excretion and lower serum urate concentrations compared with adult men. Presecretory reabsorption and tubular secretion of urate are similar in women and men. The mechanism underlying this difference is not known but both the renal handling of uric acid and the serum urate levels are not influenced by plasma 17
-estradiol concentrations (Anton et al., 1986).
Renal organic anion transporting polypeptide (oatp) mRNA expression is higher in male rat kidney than in female kidney and has been shown to be under the control of androgen and to a lesser extent estrogen (Lu et al., 1996). It is speculated that the regulation of kidney oatp expression may be necessary for modulating the renal tubular secretion of conjugated estradiol. Five forms of oatp are expressed in rat kidney. Oatp1 has a wide substrate specificity and substrates include conjugated and unconjugated bile acids, steroid hormones, organic anions such as bromosulfophthalein, and bulky organic cations such as N-(4,4-azo-n-pentyl)-21-deoxyajmalinium. OATs are multispecific organic anion transporters, with all members of the OAT family expressed in the kidney (Sekine et al., 2000). The substrates include endogenous compounds such as prostaglandins, urate and dicarboxylic acids, as well as organic anion drugs including PAH, salicylate, enalapril, and penicillin G (Dresser et al., 2001). Urakami et al. (1999) reported no significant gender-related differences in rat kidney organic anion transporter 1 (rOAT1) mRNA, but Cerrutti et al. (2002) found a significantly lower level of rOAT1 protein expression in rat kidney cortex BLM in females (40% compared with males). The lower expression of rOAT1 in kidney cortex BLM may be responsible, at least in part, for the decreased PAH secretion observed in female rats. Additionally, kidney cortex BBM isolated from female rats exhibit an increased membrane fluidity compared with BBM from male rats (Cerrutti et al., 2002); this may also contribute to the gender differences in membrane transport of substrates.
2. Cations.
Tetraethylammonium (TEA) accumulation into renal cortical slices from male rats is significantly greater than that from female rats, suggesting a gender difference in the active secretion of hydrophilic organic cations (Bowman and Hook, 1972). TEA uptake into kidney slices from male and female rats is significantly increased with testosterone treatment; estradiol treatment decreased TEA uptake in kidney slices from male rats but not female rats (Urakami et al., 2000) (Fig. 1). The apparent Km for distal tubular amantadine transport in female rats is significantly higher than that in male rats whereas the value for amantadine transport in isolated proximal tubules is not different in male and female rats. In addition, apparent Vmax estimates for amantadine uptake in proximal tubules and distal tubules are not significantly different between males and females (Wong et al., 1993). However, a small number of rats were used in this study and significant differences in transport may have been missed.
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Rat organic cation transport proteins (rOCT) are present in the kidney and are responsible for the transport of a number of organic cations, including TEA, N1-methylnicotinamide, choline, and dopamine. Expression levels of rOCT2 mRNA and protein in the male rat kidney are much higher than in females; there was no difference in rOCT1 or rOCT3 expression (Urakami et al., 1999, 2000). Treatment of male and female rats with testosterone significantly increased the expression of rOCT2 mRNA and protein in kidney and increased the TEA accumulation in kidney slices. Estradiol treatment produced a moderate decrease in kidney rOCT2 and decreased TEA accumulation in kidney slices from male, but not female, rats. Testosterone and estradiol treatment had no effect on rOCT1 mRNA or protein expression (Fig. 1). The authors suggest that OCT2 may have a physiological role in the secretion of endogenous substances. Other transporters may also play a role in the kidney transport of TEA.
P-glycoprotein (Pgp), present in the brush-border membrane of proximal tubule cells in the kidney, is involved in the renal elimination of a diverse range of lipophilic organic cations. Schinkel et al. (1994) reported a 1-fold higher expression of mdr1b in kidney isolated from female mice compared with male mice. The gene products of mdr1a and mdr1b (in mice) and MDR1 (in humans) are involved in xenobiotic transport and responsible for the multidrug resistance associated with Pgp overexpression in cancer cells. Potential gender differences in the kidney levels of Pgp in humans have not been examined; nor is there information regarding sex hormone effects on Pgp expression in the kidney. However, estrogen and progesterone may be important in the regulation of Pgp function; mRNA and protein expression for Pgp are greatly increased in the secretory luminal and glandular epithelium of the gravid murine uterus, suggesting regulation by the changes in estrogen/progesterone that occur in pregnancy (Arceci et al., 1990).
In clinical studies, the quinidine- and quinine-induced inhibition of renal amantadine clearance occurs only in healthy male subjects (Gaudry et al., 1993) and the urinary recovery at 48 h and the weight normalized renal clearance of amantadine are significantly higher in men than in women (Wong et al., 1995). The human organic cation transporters hOCT1, hOCT2, and hOCT3 have been cloned. hOCT2 is mainly expressed in the kidney but there is no information available regarding gender differences in expression (Dresser et al., 2001).
With regard to inorganic cations, the transepithelial calcium and magnesium reabsorption in the mouse cortical thick ascending limb of Henle's loop is greater in male than female animals, at both 4 and 8 weeks of age; there were no gender-related differences in NaCl transport (Wittner et al., 1997). There are sex differences in the uptake of inorganic mercury into kidney and motor neurons of mice. The uptake of mercury into the female kidney is much lower than that into the male kidney whereas inorganic mercury uptake by female motor neurons is 1.7 times greater than that in males. A smaller accumulation of mercury in the kidney of female mice may result in more circulating mercury which is available to enter muscle and taken up by distal motor axons (Pamphlett et al., 1997).
1. Anions.
Gender-associated differences in hepatic transport have been described for organic anions such as sulfobromophthalein (BSP), thymol blue, bilirubin, indocyanine green, tetrabromosulfonephthalein (TBS), and fatty acids. These organic anions are transported to a greater extent into hepatocytes isolated from the livers of female rats than male rats (Orzes et al., 1985; Sorrentino et al., 1988; Torres, 1996).
Marked differences have been reported for the hepatic uptake of a low concentration of BSP between male and female rats, both in intact animals and in isolated liver preparations and hepatocytes. The uptake rates of BSP in perfused livers, as well as the fractional plasma BSP disappearance rate, are significantly higher in females than in males. The kinetic constants of the low affinity sites are not different between genders whereas the Km of the high affinity uptake sites in females is significantly lower than that in males with no difference in Vmax, suggesting that this may be due to a different structural arrangement of the transporter or to a different membrane environment at the sinusoidal domain (Orzes et al., 1985). TBS liver uptake rate in vivo, as well as in sinusoidal liver membrane vesicles, is greater in female rats. Vmax values for TBS uptake in the membrane vesicles are similar between male and female rats while Km values in males are significantly higher than that in females (5.5 ± 0.4 versus 17 ± 4 µM) (Fig. 2), suggesting that a difference in membrane transport rates may explain the greater accumulation or uptake of TBS in female hepatocytes (Torres, 1996).
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Uptake of the glutathione conjugate of sulfobromophthalein (BSP-GSH) at steady state in single-pass liver perfusion studies is increased in female livers compared with male livers. The apparent Vmax is 48% larger in females whereas the apparent Km is similar in both sexes. The ratio of influx to efflux, which determines the equilibrium partition of BSP-GSH between the hepatocyte cytosol and plasma compartments, is significantly greater in females with no sex difference in the rate constant of biliary excretion. It has been suggested that these findings indicate that a less negative plasma membrane electrical potential in female livers may provide a more favorable electrochemical driving force for the movement of BSP-GSH into the hepatocytes in females (Sorrentino et al., 1988).
Initial oleate uptake velocity in hepatocytes isolated from female rats is also significantly greater than that from male rats. This may be due to a greater affinity of the transport system for oleate in females since no differences are observed in the Vmax value for hepatic oleate uptake as well as in the surface expression of plasma membrane fatty acid binding proteins between sexes (Sorrentino et al., 1992). Another fatty acid, palmitate, also exhibits a 2-fold higher steady-state uptake rate in livers of female rats compared with male rats (Luxon et al., 1998). Sex differences in the clearance of palmitate by human hepatocytes have been reported (Pond et al., 1996), with hepatocytes isolated from females exhibiting a 2-fold higher clearance.
Although many organic anions are transported to a greater extent by female hepatocytes, sodium-dependent taurocholate uptake is greater in male rats with a significantly higher Vmax value reported (Simon et al., 1999). Hepatic uptake of taurocholate, the major bile acid, is mainly mediated by the sodium-dependent taurocholate transporter (Ntcp) and to a lesser extent by Oatp. The initial uptake of sodium-dependent taurocholate uptake is shown over a range of concentrations (Fig. 3A). At every concentration, taurocholate uptake was greater in male hepatocytes. Suggested mechanisms that underlie the increased taurocholate transport in male hepatocytes are the greater expression of Ntcp (2-fold greater for both mRNA and protein levels) and the increased sinusoidal membrane fluidity (Lu et al., 1996). Simon et al. (1999) found that Ntcp, but not Oatp, protein content was significantly greater in males and that the expression of Ntcp was transcriptionally regulated. Hepatic Ntcp mRNA levels from female rats were 54 ± 4% of the value in males (Simon et al., 1999) (Fig. 3B). Female sinusoidal membranes had decreased fluidity (motional order) compared with male membranes, although bile canalicular membranes were not different. Liver sinusoidal membranes isolated from female rats exhibited changes in their phospholipid/fatty acid composition, in that they had a significantly increased phosphatidylethanolamine-to-phosphatidylcholine ratio. This decreased membrane fluidity in female hepatocytes may be involved in lower hepatic taurocholate uptake in females (Simon et al., 1999).
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The reduction in the hepatic transport of rifamycin SV is more pronounced in male patients than in female patients with Gilbert's syndrome. This more pronounced defect in hepatobiliary transport in male subjects may explain, at least in part, the greater frequency of Gilbert's syndrome, a pathological condition characterized by unconjugated hyperbilirubinemia, in males (Gentile et al., 1985).
Gender-related differences in the biliary excretion of the organic anion tartrazine, a food dye, has been reported in the rat (Bertagni et al., 1972). Male and female rats excrete 13 and 29%, respectively, of an intravenous dose of tartrazine by biliary excretion. Treatment of male rats with estradiol increased the excretion from 14 to 33% of the dose, although treatment of female rats with testosterone decreased the biliary excretion from 31 to 16%. Gender-related differences in the biliary excretion of S-ketoprofen have also been reported (Palylyk and Jamali, 1994). In male rats, the major route of elimination is by biliary excretion of the glucuronide conjugate, whereas in the female rat, the major route of elimination is renal clearance of the conjugate. This results in a marked difference in the amount of S-ketoprofen glucuronide eliminated in the urine in female and male rats. There are gender differences in the ATP-dependent canalicular transport of dinitrophenyl-glutathione conjugate (Srivastava et al., 1999). Transport is higher in membrane vesicles isolated from male mice compared with female mice. Additionally, whereas only one transport system is present in male mouse cLPM for the transport of dinitrophenyl-glutathione, there is both high and low affinity systems present in cLPM isolated from female mice. The ATP-dependent transport of organic anions, including glucuronide and glutathione conjugates, occurs by multidrug resistance-associated protein 2 (MRP2), also known as the canalicular multispecific organic anion transporter (cMOAT). MRP2 is the major transporter responsible for secretion of bilirubin glucuronides into bile; gender differences in the expression of MRP2 have not been examined.
2. Cations.
Pgp is present on the canalicular membrane of hepatocytes and involved in the biliary excretion of phospholipids, cholesterol, and a wide variety of lipophilic organic cations. Hepatic expression of the gene product of mdr2 in female rats is 7-fold higher than in male rats (Furuya et al., 1994). This isoform of Pgp is mainly involved in phospholipid transport across the canalicular membrane. Piquette-Miller et al. (1998) and Salphati and Benet (1998) reported higher levels of total mdr gene products in female rat livers compared with male livers. Gender differences in mdr mRNA levels were also seen. Male livers contained more than 2-fold higher levels of mdr1b and female livers contained higher levels (approximately 35–50%) of mdr1a and mdr2 (Piquette-Miller et al., 1998; Salphati and Benet, 1998). In humans, hepatic Pgp (total) protein expression is 2-fold higher in men than in women (Schuetz et al., 1995), suggesting that the drug disposition of Pgp substrates could be different between genders, resulting in differences in drug efficacy and toxicity between males and females. Interestingly, there are gender-related differences in Pgp expression and functional activity in peripheral blood samples of subjects with B-type chronic lymphocytic leukemia, with significantly more men (89%) than women (48%) being MDR1 phenotype-positive (Steiner et al., 1998). These findings are consistent with the overall better prognosis for women with chronic lymphocytic leukemia than for men (Steiner et al., 1998).
Very little is known regarding gender-related differences in intestinal uptake and drug bioavailability. Clinical studies have reported an increased bioavailability of both iron and ethanol in women but these gender-related differences likely do not involve differences in intestinal transporters. For ethanol, the increased bioavailability is likely due to decreased gastric metabolism of alcohol in women (Lieber et al., 1994). Decreases in both the rate and extent of absorption of acetaminophen occur in late pregnancy; this is likely due to decreases in the rate of gastric emptying (Galinsky and Levy, 1984).
A gender-related difference has been documented in the transport of calcium in the intestine. Kinetic analysis of calcium transport across the rat intestine has shown that there are two transport processes, one of which is saturable and the other nonsaturable. The saturable transport process is regulated by vitamin D and is predominantly located in the proximal intestine whereas the nonsaturable process is not vitamin D-dependent and has similar capacity throughout the intestine (Bronner et al., 1986). Intestinal calcium transport is significantly greater in male rats than in female rats in a vitamin D-sufficient condition, although it is comparable between sexes in the presence of vitamin D deficiency. Vitamin D deficiency produces a markedly lower intestinal transport of calcium in male rats but not in female rats. This observation suggests that calcium transport in the intestine of female rats, unlike male rats, is mediated by a vitamin D-independent mechanism at the calcium intake levels studied in this investigation (Uhland-Smith and DeLuca, 1993).
Total intestinal absorption of calcium is enhanced during pregnancy and lactation in vitamin D-deficient rats. Intestinal calcium absorption during the rat estrous cycle is highest during estrus and lowest during diestrus following the administration of both high and low calcium diets. Since the highest serum levels of estradiol, progesterone, prolactin, follicle-stimulating hormone, and luteinizing hormone are present during estrus (Butcher et al., 1974; Brommage et al., 1990), the greatest intestinal absorption of calcium observed during estrus may be related, either directly or indirectly, to any one of several sex hormones (Brommage et al., 1993). Intestinal mucosal cells contain estrogen receptors, and calcium uptake in duodenal cells is significantly enhanced by about 60% by 17-estradiol at a concentration of 10 nM (Arjmandi et al., 1993). Administration of 17-estradiol at a dose of 40 µg/kg b.wt./day for 21 days significantly elevated intestinal absorption of calcium in female rats whereas serum levels of 1,25-dihydroxyvitamin D were unaltered (Arjmandi et al., 1994). These findings suggest that transluminal calcium uptake is promoted by a direct action of 17-estradiol on the intestinal tract with no increase in the circulating levels of 1,25-dihydroxyvitamin D (Arjmandi et al., 1993, 1994).
The implications of these observations are as follows. First, estrogen may play an important physiological role in regulation of intestinal calcium absorption. High estrogen levels during pregnancy and estrus may promote calcium absorption, and estrogen deficiency in menopause may result in calcium malabsorption by a direct action on the intestine. The malabsorption of calcium in the intestine as a result of ovarian hormone deficiency in postmenopausal women is often associated with osteoporosis characterized by bone loss (Heaney et al., 1978; Gallagher et al., 1979, 1980; Gallagher, 1990). Second, the rate and extent of intestinal calcium absorption may be modulated by compounds that block or mimic estrogen action.
Aluminum, at a concentration of 2 µM, significantly decreases mucosa-to-serosa calcium influx in duodenal everted sacs both of male and female rats compared with aluminum-free controls; however, the percentage of reduction in females (31.2%) is greater than that in males (17.8%). The sensitivity to the inhibitory effect of aluminum on duodenal calcium flux is raised with increasing serum levels of 17-estradiol in ovariectomized female rats with no alterations in the maximal response, whereas the effect of aluminum on calcium flux in duodenal sacs is not dependent of serum testosterone levels in castrated male rats injected with testosterone. These results demonstrate that there are gender-associated differences in the inhibitory effect of aluminum on transluminal calcium transport in the duodenum of the rat (Orihuela et al., 1996).
There have been few studies that have examined the potential for gender-related differences in transport across the blood-brain barrier (BBB). 17-Estradiol treatment of ovariectomized rats increases 2-deoxyglucose uptake into brain, which is likely due to the increase in the mRNA and protein expression of glucose transporter 1 (GLUT-1) in the BBB epithelium (Shi and Simpkins, 1997). These results support a modulatory role for estrogens in the brain transport of glucose.
Both Pgp and MRP1 are present in the BBB epithelium and are responsible for the active efflux of drugs from the brain, minimizing brain exposure to many organic anions and cations. Although Pgp exhibits gender differences in expression in liver, this has not been examined for the BBB. Gender differences in the BBB uptake of verapamil have been reported in mice where female mice have increased functional Pgp activity, resulting in decreased verapamil influx into the brain (Dagenais et al., 2001). However, gender differences in uptake were not observed for two other Pgp substrates, morphine or quinidine (Dagenais et al., 2001), so the significance of these findings is unknown.
The effect of gender on the reuptake of dopamine (DA) by the sodium-dependent DA transporter into nerve terminals, the primary mechanism for inactivation of DA following its release into the synapse, has been examined. An increased synaptosomal DA reuptake in the anterior hypothalamus is observed in ovariectomized rats treated with estradiol due to an increase in the number of DA uptake binding sites (Cardinali and Gomez, 1977). The maximal binding density (Bmax) of striatal DA uptake sites is significantly elevated 15 and 30 min after an injection of a physiological dose of 17-estradiol in ovariectomized rats with no change in the binding affinity (Kd) of the DA uptake sites. There is no effect of progesterone on striatal DA uptake after progesterone treatment of ovariectomized rats. The increase of DA uptake binding sites by the administration of 17-estradiol is rapid and short-lasting and is associated with peak 17-estradiol plasma levels, suggesting most likely a membrane-linked nongenomic effect of 17-estradiol (Morissette et al., 1990). When ovariectomized rats are chronically treated with 17-estradiol and/or progesterone at pharmacological doses, DA uptake site density in the striatum is significantly increased by 16 to 23% without an alteration in the binding affinity, most likely due to an increased synthesis of the DA transporter by a genomic effect of these female sex hormones. In addition, chronic exposure to 17-estradiol and/or progesterone up-regulates the DA uptake sites in the nigrostriatal dopaminergic pathway whereas the nucleus accumbens and the substantia nigra pars reticula are not affected (Morissette and Di Paolo, 1993a). Striatal DA uptake site density is significantly lower in normal male rats, gonadectomized male rats, and ovariectomized female rats compared with normal female rats and fluctuates during the female estrous cycle with a peak occurring in the morning of proestrus when estradiol is elevated and progesterone is low, suggesting an up-regulation of striatal DA uptake sites by estradiol (Morissette and Di Paolo, 1993b). This agrees with the findings of an investigation examining the effect of acute treatment with 17-estradiol (Morissette et al., 1990). It has also been shown that 17-estradiol increases DA uptake in mesencephalic neurons isolated from females but not in male neurons, and male sex hormones, testosterone and dihydrotestosterone, have no effect (Engele et al., 1989). In humans, DA and serotonin (5-hydroxytryptamine; 5-HT) transporter availability is greater in females compared with males, as determined by single photon emission computed tomography imaging using an analog of cocaine (CIT) that labels DA and 5-HT transporters (Staley et al., 2001). Therefore, gonadal hormones may play an important role in the effects of psychoactive drugs acting on neuronal DA uptake sites and modulation of the DA transporter by these hormones will represent a source of interindividual variability in the treatment of neuropsychiatric disorders and neurologic diseases such as Parkinson's disease (Cardinali and Gomez, 1977; Engele et al., 1989; Morissette et al., 1990; Morissette and Di Paolo, 1993a,b).
A sexual dimorphism in the density of norepinephrine transporters has been demonstrated in the frontal cortex of rats, with males having significantly fewer binding sites than females, whereas the binding affinity of the uptake sites was not different between genders (Vathy et al., 1997). 5-HT uptake in the anterior and middle hypothalamus of intact female rats exceeds significantly that in intact male rats (by about 30–40%) and is similar to that in neonatally castrated adult rats (Fig. 4), suggesting that androgens may play a key role in the development of the hypothalamic serotoninergic system over the neonatal period by inhibiting either the serotoninergic axon ingrowth to the hypothalamus or the ramifications of the axonal terminal portions (Borisova et al., 1996). Estradiol treatment stimulates a significant increase in the density of 5-HT2A binding sites in the anterior frontal, anterior cingulate and piriform cortex, the olfactory tubercle, the nucleus accumbens and the lateral dorsal raphe nucleus, areas of brain concerned with cognition, emotion, and motor control, suggesting that the antidepressant action of estrogen may be mediated by a serotoninergic mechanism (Fink et al., 1996).
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The rate of glucose uptake in skeletal muscle, under hyperinsulinemic and normoglycemic conditions, is significantly greater in women than in men (Fig. 5), suggesting an increased sensitivity to insulin in women (Nuutila et al., 1995). Basal and maximal insulin-stimulated glucose transport is also significantly higher in adipocytes isolated from female rats and human female subjects compared with males (Foley et al., 1984). In skeletal muscle, fatty acid transport protein-1 (FATP-1) mRNA levels are higher in lean women than in lean men (2.2 ± 0.1 versus 0.6 ± 0.2 attomoles/µg of total RNA, p < 0.01). FATP-1 mRNA was significantly decreased in skeletal muscle of obese women, but no change in FATP-1 expression was seen in men. Additionally, insulin infusion reduced FATP-1 mRNA in muscle of lean women, but not in men (Binnert et al., 2000). This study indicates that lean women may be able to utilize lipids to a greater extent than men, although whether differences in FATP-1 mRNA result in corresponding differences in FATP-1 protein expression is not known.
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A marked difference in the splanchnic uptake of chylomicron triglyceride is observed between men and women. Chylomicron uptake in the splanchnic tissues in men and women accounts for 71% and 20% of meal triglyceride disposal, respectively, indicating greater meal fatty acid storage in visceral adipose tissue in men and gender-specific differences in body fat distribution (Nguyen et al., 1996).
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III. Conclusions |
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Gender differences in membrane transport in humans are not always consistent with differences reported in animal studies. For example, Pgp, an ATP-dependent efflux pump present in cancer cells and excretory organs, demonstrates a higher hepatic expression in men than in women (Schuetz et al., 1995), but opposite changes have been reported in rats (Furuya et al., 1994; Piquette-Miller et al., 1998). In addition, gender differences in the urinary excretion of zenarestat are observed in mice and rats but not in dogs and humans (Tanaka et al., 1992). This emphasizes the importance of performing studies in humans to evaluate the effect of gender.
Gender-associated differences in the nature and prevalence of many diseases may be explained, at least in part, by the differences in the transport processes of substrates between male and female subjects. In addition, these gender-related differences in transport systems may be responsible, at least in part, for interindividual variability in drug disposition, therapeutic response, and drug toxicity. Research is needed to evaluate potential gender differences in regulation, expression, and activity of known transport proteins involved in the uptake or secretion of both endogenous and exogenous compounds.
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1 Current address: College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul, 120-750, South Korea. 
1 Abbreviations: PAH, p-aminohippurate; Oatp, organic anion transporter polypeptide; TEA, tetraethylammonium; rOCT, rat organic cation transport protein; hOCT, human organic cation transport protein; BBM, brush-border membrane; BLM, basolateral membrane; BSP, sulfobromophthalein; TBS, tetrabromosulfonephthalein; BSP-GSH, glutathione conjugate of sulfobromophthalein; Ntcp, sodium-dependent taurocholate transporter; cLPM, canalicular liver plasma membrane; MRP, multidrug resistance-associated protein;; Pgp, P-glycoprotein; DA, dopamine; BBB, blood-brain barrier; 5-HT, 5-hydroxytryptamine; FATP-1, fatty acid transport protein-1.
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Anton FM, Garcia Puig J, Ramos T, Gonzalez P, and Ordas J (1986) Sex differences in uric acid metabolism in adults: evidence for a lack of influence of estradiol-17 beta (E2) on the renal handling of urate. Metabolism 35: 343-348.[CrossRef][Medline]
Arceci RJ, Baas F, Raponi R, Horwitz SB, Housman D, and Croop JM (1990) Multidrug resistance gene expression is controlled by steroid hormones in the secretory epithelium of the uterus. Mol Reprod Dev 25: 101-109.[CrossRef][Medline]
Arjmandi BH, Hollis BW, and Kalu DN (1994) In vivo effect of 17 beta-estradiol on intestinal calcium absorption in rats. Bone Miner 26: 181-189.[Medline]
Arjmandi BH, Salih MA, Herbert DC, Sims SH, and Kalu DN (1993) Evidence for estrogen receptor-linked calcium transport in the intestine. Bone Miner 21: 63-74.[Medline]
Beierle I, Meibohm B, and Derendorf H (1999) Gender differences in pharmacokinetics and pharmacodynamics. Int J Clin PharmacolTher 37: 529-547.[Medline]
Benincosa LJ, Sagawa K, Massey LK, and Morris ME (1995) Effects of acute caffeine ingestion and menopause on sulfate homeostasis in women. Life Sci 57: 1497-1505.[CrossRef][Medline]
Bertagni P, Hirom PC, Millburn P, Osiyemi FO, Smith RL, Turbert HB, and Williams RT (1972) Sex and species differences in the biliary excretion of tartrazine and lissamine fast yellow in the rat, guinea-pig and rabbit. The influence of sex hormones on tartrazine excretion in the rat. J Pharm Pharmacol 24: 620-624.[Medline]
Binnert C, Koistinen HA, Martin G, Andreelli F, Ebeling P, Koivisto VA, Laville M, Auwerx J, and Vidal H (2000) Fatty acid transport protein-1 mRNA expression in skeletal muscle and in adipose tissue in humans. Am J Physiol Endocrinol Metab 279: E1072-E1079.
Bonate PL (1991) Gender-related differences in xenobiotic metabolism. J Clin Pharmacol 31: 684-690.[Medline]
Borisova NA, Proshlyakova EV, Sapronova AY, and Ugrumov MV (1996) Androgen-dependent sex differences in the hypothalamic serotoninergic system. Eur J Endocrinol 134: 232-235.[Abstract]
Bowman HM and Hook JB (1972) Sex differences in organic ion transport by rat kidney. Proc Soc Exp Biol Med 141: 258-262.[Medline]
Brommage R, Baxter DC, and Gierke LW (1990) Vitamin D-independent intestinal calcium and phosphorus absorption during reproduction. Am J Physiol 259: G631-G638.
Brommage R, Binacua C, and Carrie AL (1993) Ovulation-associated increase in intestinal calcium absorption during the rat estrous cycle is blunted by ovariectomy. Biol Reprod 49: 544-548.[Abstract]
Bronner F, Pansu D, and Stein WD (1986) An analysis of intestinal calcium transport across the rat intestine. Am J Physiol 250: G5610-G569.
Butcher RL, Collins WE, and Fugo NW (1974) Plasma concentration of LH, FSH, prolactin, progesterone and estradiol-17beta throughout the 4-day estrous cycle of the rat. Endocrinology 94: 1704-1708.[Medline]
Cardinali DP and Gomez E (1977) Changes in hypothalamic noradrenaline, dopamine and serotonin uptake after oestradiol administration to rats. J Endocrinol 73: 181-182.[Medline]
Carter AL and Stratman FW (1982) Sex steroid regulation of urinary excretion of carnitine in rats. J Steroid Biochem 17: 211-216.[CrossRef][Medline]
Cerrutti JA, Brandoni A, Quaglia NB, and Torres AM (2002) Sex difference in p-aminohippuric acid transport in rat kidney: role of membrane fluidity and expression of OAT1. Mol Cell Biochem 233: 175-179.[CrossRef][Medline]
Cerrutti JA, Quaglia NB, and Torres AM (2001) Characterization of the mechanisms involved in the gender differences in p-aminohippurate renal elimination in rats. Can J Physiol Pharmacol 79: 805-813.[CrossRef][Medline]
Dagenais C, Zong J, Ducharme J, and Pollack GM (2001) Effect of mdr1a P-glycoprotein gene disruption, gender and substrate concentration on brain uptake of selected compounds. Pharm Res 18: 957-963.[CrossRef][Medline]
Dresser MJ, Leabman MK, and Giacomini KM (2001) Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J Pharm Sci 90: 397-421.[CrossRef][Medline]
Engele J, Pilgrim C, and Reisert I (1989) Sexual differentiation of mesencephalic neurons in vitro: effects of sex and gonadal hormones. Int J Dev Neurosci 7: 603-611.[CrossRef][Medline]
Fink G, Sumner BE, Rosie R, Grace O, and Quinn JP (1996) Estrogen control of central neurotransmission: effect on mood, mental state and memory. Cell Mol Neurobiol 16: 325-344.[CrossRef][Medline]
Fletcher CV, Acosta EP, and Strykowski JM (1994) Gender differences in human pharmacokinetics and pharmacodynamics. J Adolesc Health 15: 619-629.[CrossRef][Medline]
Foley JE, Kashiwagi A, Chang H, Huecksteadt TP, Lillioja S, Verso MA, and Reaven G (1984) Sex difference in insulin-stimulated glucose transport in rat and human adipocytes. Am J Physiol 246: E211-E215.
Furuya KN, Gebhardt R, Schuetz EG, and Schuetz JD (1004) Isolation of rat pgp3 cDNA: evidence for gender and zonal regulation of expression in the liver. Biochim Biophys Acta 1219: 636-644.
Galinsky RE and Levy G (1984) Absorption and metabolism of acetaminophen shortly before parturition. Drug Intell Clin Pharm 18: 977-979.[Abstract]
Gallagher JC (1990) The pathogenesis of osteoporosis. Bone Miner 9: 215-227.[CrossRef][Medline]
Gallagher JC, Riggs BL, and DeLuca HF (1980) Effect of estrogen on calcium absorption and serum vitamin D metabolites in postmenopausal osteoporosis. J Clin Endocrinol Metab 51: 1359-1364.[Abstract]
Gallagher JC, Riggs BL, Eisman J, Hamstra A, Arnaud SB, and DeLuca HF (1979) Intestinal calcium absorption and serum vitamin D metabolites in normal subjects and osteoporotic patients: effect of age and dietary calcium. J Clin Investig 64: 729-736.
Gaudry SE, Sitar DS, Smyth DD, McKenzie JK and Aoki FY (1993) Gender and age as factors in the inhibition of renal clearance of amantadine by quinine and quinidine. Clin Pharmacol Ther 54: 23-27.[Medline]
Gentile S, Persico M, Baldini G, Lunazzi G, Tiribelli C, and Sottocasa GL (1985) The implication of bilitranslocase function in the impaired rifamycin SV metabolism in Gilbert's syndrome. Clin Sci (Lond) 68: 675-680.[Medline]
Gleiter CH and Gundert-Remy U (1996) Gender differences in pharmacokinetics. Eur J Drug Metab Pharmacokinet 21: 123-128.[Medline]
Hanhijarvi H, Ophaug RH, and Singer L (1982) The sex-related difference in perfluorooctanoate excretion in the rat. Proc Soc Exp Biol Med 171: 50-55.[Medline]
Harris RZ, Benet LZ, and Schwartz JB (1995) Gender effects in pharmacokinetics and pharmacodynamics. Drugs 50: 222-239.[Medline]
Heaney RP, Recker RR, and Saville PD (1978) Menopausal changes in calcium balance performance. J Lab Clin Med 92: 953-963.[Medline]
Ifudu O, Uribarri J, Rajwani I, Vlacich V, Reydel K, Delosreyes G, and Friedman EA (2001) Gender modulates responsiveness to recombinant erythropoietin. Am J Kidney Dis 38: 518-522.[Medline]
Kaasinen V, Nagren K, Hietala J, Farde L, and Rinne JO (2001) Sex differences in extrastriatal dopamine d(2)-like receptors in the human brain. Am J Psychiatry 158: 308-311.
Kashuba AD and Nafziger AN (1998) Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. Clin Pharmacokinet 34: 203-218.[CrossRef][Medline]
Kleinman LI, Loewenstein MS, and Goldstein L (1966) Sex difference in the transport of p-aminohippurate by the rat kidney. Endocrinology 78: 403-406.[Medline]
Lee HJ, Balasubramanian SV, and Morris ME (1999a) Effect of pregnancy, postnatal growth and gender on renal sulfate transport. Proc Soc Exp Biol Med 221: 336-344.[Abstract]
Lee HJ, Balasubramanian SV, Murer H, Biber J, and Morris ME (1999b) Modulation of sulfate renal transport by alterations in cell membrane fluidity. J Pharm Sci 88: 976-980.[CrossRef][Medline]
Levy G (1998) Predicting effective drug concentrations for individual patients. Determinants of pharmacodynamic variability. Clin Pharmacokinet 34: 323-333.[CrossRef][Medline]
Lieber CS, Gentry RT, and Baraona E (1994) First pass metabolism of ethanol. Alcohol Suppl 2: 163-169.
Lu R, Kanai N, Bao Y, Wolkoff AW, and Schuster VL (1996) Regulation of renal oatp mRNA expression by testosterone. Am J Physiol 270: F332-F337.
Luxon BA, Holly DC, Milliano MT, and Weisiger RA (1998) Sex differences in multiple steps in hepatic transport of palmitate support a balanced uptake mechanism. Am J Physiol 274: G52-G61.
Morissette M, Biron D, and Di Paolo T (1990) Effect of estradiol and progesterone on rat striatal dopamine uptake sites. Brain Res Bull 25: 419-422.[CrossRef][Medline]
Morissette M and Di Paolo T (1993a) Effect of chronic estradiol and progesterone treatments of ovariectomized rats on brain dopamine uptake sites. J Neurochem 60: 1876-1883.[Medline]
Morissette M and Di Paolo T (1993b) Sex and estrous cycle variations of rat striatal dopamine uptake sites. Neuroendocrinology 58: 16-22.[Medline]
Nguyen TT, Mijares AH, Johnson CM, and Jensen MD (1996) Postprandial leg and splanchnic fatty acid metabolism in nonobese men and women. Am J Physiol 271: E965-E972.
Nuutila P, Knuuti MJ, Maki M, Laine H, Ruotsalainen U, Teras M, Haaparanta M, Solin O, and Yki-Jarvinen H (1995) Gender and insulin sensitivity in the heart and in skeletal muscles. Studies using positron emission tomography. Diabetes 44: 31-36.[Abstract]
Orihuela D, Carnovale CE, Monti JA, and Carrillo MC (1996) Sex-related differences in the effect of aluminum on calcium transport in the small intestine of the rat. Toxicol Lett 85: 165-171.[CrossRef][Medline]
Orzes N, Bellentani S, Aldini R, Simoni P, Ferretti I, Lunazzi GC, Sottocasa GL, and Tiribelli C (1985) Sex differences in the hepatic uptake of sulphobromophthalein in the rat. Clin Sci (Lond) 69: 587-593.[Medline]
Palylyk EL and Jamali F (1994) Influence of sex on the stereoselective probenecid-ketoprofen interaction in the rat. J Pharm Sci 83: 1184-1185.[CrossRef][Medline]
Pamphlett R, Ewan KB, McQuilty R, and Waley P (1997) Gender differences in the uptake of inorganic mercury by motor neurons. Neurotoxicol Teratol 19: 287-293.[CrossRef][Medline]
Piquette-Miller M, Pak A, Kim H, Anari R, and Shahzamani A (1998) Decreased expression and activity of P-glycoprotein in rat liver during acute inflammation. Pharm Res 15: 706-711.[CrossRef][Medline]
Pond SM, Gordon RA, and Bass L (1996) Sex differences in initial clearance of palmitate by human hepatocytes. Eur J Clin Investig 26: 76-81.[CrossRef][Medline]
Salphati L and Benet LZ (1998) Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers. Biochem Pharmacol 55: 387-395.[CrossRef][Medline]
Sato M, Suzaka H, and Miyazaki H (2000) Sex-related differences in urinary excretion of egualen sodium in rats. Drug Metab Dispos 28: 21-27.
Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, Mol CA, van der Valk MA, Robanus-Maandag EC, te Riele HP, et al. (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77: 491-502.[CrossRef][Medline]
Schuetz EG, Furuya KN, and Schuetz JD (1995) Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 275: 1011-1018.
Sekine T, Cha SH, and Endou H (2000) The multispecific organic anion transporter (OAT) family. Pfluegers Arch 440: 337-350.
) and oophorectomized (ovx) female (•) rats, and initial uptake of [3H]taurocholate was measured at 60 s in the presence and absence of sodium. These data were used to estimate the maximal uptake (Vmax) and the Michaelis-Menten constant (Km) values. Results are means ± S.E. of three independent experiments in each group. B, immunoblot analysis of sinusoidal membrane proteins from liver homogenates (A) and liver sinusoidal membrane fractions (B), from male and female rats. Liver sinusoidal proteins were identified using specific antibodies. Male (
) and female (
) hepatic steady-state levels of Ntcp, Oatp, and Na+-K+-ATPase are shown in panel C. Male levels were set at 100%. Results are mean ± S.E. of 4 to 12 separate determinations. *, p < 0.01. Reprinted with permission (Simon et al., 1999
