Sex and strain differences in hepatic debrisoquine 4-hydroxylase activity of the rat

Debrisoquine 4-hydroxylase activity in microsomal fractions from liver of DA, Fischer, and Lewis rats has been determined. Activity in DA rats is up to 14-fold lower than in animals from the corresponding sex of the other strains. There is also a major sex difference in debrisoquine 4-hydroxylase activity of all three strains. Kinetic analysis revealed at least two components of activity, even in the liver of female DA rats. Thus, the decreased activity in these animals could not be attributed to the absence of a single isozyme of cytochrome P-450. Michaelis-Menten analysis revealed that both components of activity were impaired in these animals. Debrisoquine 4-hydroxylase activity was inducible by both 3-methylcholanthrene and phenobarbital in DA and Fischer rats. However, in the DA rat, activity was inducible only at higher substrate concentrations (greater than 50 microM). It is concluded that the DA rat differs from other strains in at least three different isozymes of cytochrome P-450 that can catalyze the 4-hydroxylation of debrisoquine. At least one of these is male-specific and at least one is inducible. The DA rat might provide a suitable model in which to predict which substrates might show impaired oxidation in the poor metabolizer phenotype, but studies on the molecular mechanism of the polymorphism in this strain would appear to have doubtful validity for the polymorphism in man.     

The formation of methaemoglobin by 4-aminopropiophenone (PAPP) and 4-(N-hydroxy) aminopropiophenone.

Oral dosing of rats with the cyanide antidote 4-aminopropiophenone (PAPP), brought about peak methaemoglobin levels at 15-40 min, but peak levels were attained at at 15-25 min after intravenous dosing. After both oral and intravenous administration at equimolar doses, 4-(N-hydroxy)aminopropiophenone (PHAPP), the putative methaemoglobin-producing metabolite of PAPP, produced higher peak levels of methaemoglobin than PAPP. Plasma from rats injected with PAPP was capable of forming methaemoglobin when added to naive rat erythrocytes. The identity of the metabolite responsible is discussed.     

Sex differences in the pharmacokinetics of salicylates

The kinetics of disposition of total and free salicylic acid (SA) in blood plasma was evaluated after single and multiple oral administration of acetylsalicylic acid (ASA) to healthy female and male volunteers. In both single and multiple dose studies significant sex differences were found in the plasma levels of SA, which were due, at least in part, to individual, sex-determined differences in the rate of absorption and elimination of SA; a slower absorption rate in men reduced the magnitude of the peak plasma levels of SA. The corresponding area under concentration-time curves were always significantly lower. The elimination rate of SA in men was increased in comparison with women. The higher plasma clearance in men resulted from the kinetics of absorption and elimination. The sex differences appear to be clinical significance, since men achieved lower plasma levels of SA than women after the same weight-adjusted dose of ASA.     

Bioactivation of the cyanide antidote 4-aminopropiophenone (4-PAPP) by human and rat hepatic microsomal enzymes: effect of inhibitors

The bioactivation of the cyanide antidote methaemoglobin former 4-aminopropiophenone (4-PAPP) was studied using rat and human microsomes. With rat liver and NADPH in single and two-compartment systems, dapsone and benzocaine were more potent methaemoglobin generators compared with 4-PAPP. In the single compartment studies, the order of potency of inhibition of 4-PAPP-mediated methaemoglobin formation was cimetidine (1.5 mM)>isoniazid (500 μM)/diethyldithiocarbamate (DDC, 1 mM)>erythromycin (500 μM). Human liver microsomal activation of 4-PAPP in the two-compartment system was partially inhibited by both DDC and cimetidine. These preliminary studies suggest that 4-PAPP may be metabolised by CYP 2C11, 2E1 and 3A in the rat and CYP 2C, 2E1 and probably 3A4 in man.     

Sex differences in sulfobromophthalein-glutathione transport by perfused rat liver

Sex differences have been described in the hepatic transport of many organic anions. Proposed mechanisms include differences in the rate of metabolism, in the degree of binding to cytoplasmic proteins, and in the rate of membrane transport. To better define these factors, we used the perfused rat liver to study the hepatic transport of the glutathione conjugate of sulfobromophthalein (BSP-GSP), a model compound that does not require metabolism for excretion. Hepatic transport of BSP-GSH was saturable for both sexes. Clearance of BSP-GSH from 1% albumin solutions at steady-state was 35-52% greater in female livers than in male livers, and reflected a 47% larger apparent Vmax with no change in the apparent Km. Analysis of the rate of disappearance of BSP-GSH from recirculating perfusate and its appearance in bile using a simple two-compartment model indicated that the ratio of influx to efflux was greater in female livers. These findings are compatible with sex-related differences in the electrochemical driving forces for BSP-GSH uptake.     

Sex differences in the cumulative incidence of substance use by birth cohort

BackgroundMen present higher overall rates of substance use and abuse than women; yet, evidence suggests that an increase of substance use by the younger cohorts of women in recent decades is narrowing this gap in western societies. Moreover, younger cohorts may also be reporting earlier initiation of substance use, representing an increased risk for developing substance-related problems. With this study we intend to identify changes in the patterns of substance use of men and women in Spain for public health policy, planning and intervention.MethodsSex differences in the cumulative incidence of alcohol, tobacco, cannabis and cocaine were examined by birth cohort using a combined sample of individuals aged 15–64 years from eight editions of the Spanish National Survey on Drugs (1995–2009).ResultsInitiation of substance use in Spain is progressively taking place at younger ages, particularly among women. The gender-gap of life-time occurrence of substance use is narrowing (cannabis and cocaine) almost closing (alcohol) and even reversing (tobacco) in the youngest cohort.ConclusionThese results reflect the particular evolution and trends of Spanish society regarding substance use. Women's increased use of substances and the earlier age of initiation of substance use by both sexes present particular challenges for prevention and treatment of future substance-related problems. The trends registered for legal and illegal substances would require re-evaluation of existing prevention policies.     

Sex differences in pharmacokinetics of antidepressants

INTRODUCTION: Sex differences have been identified in antidepressant treatment; however, it remains unclear to what extent pharmacokinetics contributes to these differences. As current antidepressant pharmacotherapy is less than optimal, understanding the role of sex in pharmacokinetics may substantially contribute to a gender-based optimized treatment. AREAS COVERED: An unrestricted PubMed literature search on antidepressant pharmacokinetics and sex was performed. Sex differences in absorption, distribution, metabolism and elimination of antidepressants, as well as the interaction of sex with age, genetic polymorphisms and gonadal hormones are discussed. We also provide an overview of how each antidepressant presents a particular sex-differentiated pharmacokinetic profile. Most antidepressants present to some extent pharmacokinetic sex differences, which often are further accentuated by gonadal hormones. In most cases, women, particularly elderly women, are expected to have higher exposure to antidepressants when dosed in a similar way as men. EXPERT OPINION: Although the available pharmacokinetic evidence indicates that women should receive lower doses of antidepressants and men should receive higher doses, current guidelines do not recommend dose adjustment, because these sex differences are considered to be clinically insignificant. Unless we understand the link between pharmacokinetics and pharmacodynamics of antidepressants, it will be difficult to determine whether sex differences are of clinical importance or not. Thus, further systematic and particularly focused research is needed on sex differences in pharmacokinetics.     

Sex differences in stereotyped behavior in the rat

Neurologically intact female rats exhibited more intense and more prolonged stereotyped behavior in response to 5 mg/kg doses of d-amphetamine than males. They also displayed greater stimulation of activity in response to 1.5 mg/kg doses of the drug. Prior treatment with intrastriatal injections of 6-hydroxydopamine (6HDA) eliminated the sex difference in response to 5 but not to 1.5 mg/kg amphetamine. Neither intact nor 6HDA treated rats differed in the amount of stereotyped behavior elicited by the dopamine agonist apomorphine suggesting that the sex difference in amphetamine-elicited stereotypy is not the result of differences in strial receptor mechanisms. The present results could arise from sex differences in amphetamine uptake and metabolism which have been described recently although other explanations are possible.     

Sex differences in sympathetic-adrenal medullary reactions induced by different stressors

Male and female university students were exposed to two different stressors in each of two 110-min sessions, i.e., a cognitive task (color-word conflict) and repeated venipuncture. Catecholamine excretion, heart rate, and subjective reactions were measured. Control values were obtained under conditions of relaxation in the laboratory. Subjects of both sexes responded to both stressors by increased heart rate and feelings of unpleasantness and distress. The pattern of adrenaline excretion, however, differed between sexes: in males both stressors induced a significant increase, whereas in females adrenaline excretion remained on the same level under the two stress conditions as during relaxation. Noradrenaline excretion was not systematically affected by either stressor in either sex group.     

阿片类药物不良反应的性别差异

阿片类药物是临床中广泛用于治疗中度至重度疼痛的药物。阿片类药物不良反应的性别差异近年日益受到重视,其中包括药物在呼吸抑制、胃肠道反应、心血管反应、镇痛耐受性及药物依赖性等方面的差异。进一步研究阿片类药物不良反应的性剐差异,将有助于更好地实施个体化用药。     

Sex differences in drug evaluations.

Twenty normal, nonobese subjects (10 males and 10 female) were administered a battery of seven psychomotor tests as well as affect checklists and physiological measurements on 6 alternate days. Subjects performed the entire battery predrug and at 45,90, and 135 min postdrug. Fenfluramine, dextroamphetamine, two combined doses of the drugs, and a placebo were given in a double-blind, repeated measures design. Findings revealed significant sex-based differences in initial performance on five of the seven psychomotor tasks and in two physiological measures, with males performing at higher levels than females. Additionally, sex differences in postdrug changes were found in three psychomotor and two physiological measures, with females evidencing greater change scores than males.     

Sex differences in tobacco withdrawal syndrome

Prospective data from an inpatient (n = 20) and outpatient (n = 50) study were examined for sex differences in tobacco withdrawal symptoms. With each subject serving as his/her own control, changes in a wide range of physiological, psychological and behavioral measures were determined from baseline to tobacco abstinence condition. For all 46 measures, no statistically significant differences between men and women were found in either the number or severity of tobacco withdrawal symptoms.     

Sex differences in sensitivity to seizures elicited by pentylenetetrazol in mice

Sex differences in sensitivity to seizures elicited by intraperitoneally injected pentylenetetrazol (PTZ) were studied in 240 (120 males and 120 females) adult Swiss mice. Animals were separated into four groups according to the dose that was injected: 40, 50, 60 and 70 mg/kg. Seizure severity was expressed by the following scoring scale: (0) no abnormal behavior; (1) myoclonus; (2) running bouncing (RB) clonus; (3) tonic hind limb extension (THE). The analyses of the dose-response curves indicated that females were more susceptible than males when the 50- and 60-mg/kg doses were used. Specifically, females often displayed RB clonus, while males frequently displayed only myoclonus or no abnormal behavior. No significant sex differences were demonstrated when either the 40- or the 70-mg/kg doses were used. These data indicate that, for a specific range of doses, sex differences in seizure susceptibility can be clearly demonstrated with the use of intraperitoneally injected PTZ. In this sense, this method could be used as a tool to investigate the role played by sexual hormones in regulating the sensitivity of the gamma-aminobutiric acid (GABA(A)) receptor complex (GRC).     

Sex differences in the subjective tolerability of antipsychotic drugs

In recent years, research efforts have been directed to better characterize the subjective experience of taking psychotropic drugs. This study investigated the sex difference in the subjective tolerability of antipsychotic drugs. Participants were recruited from patients under the care of psychiatric services serving geographical catchment areas in Croydon (UK), Verona (Italy), Amsterdam (Netherlands), and Leipzig (Germany). Clinically unstable patients with a clinical diagnosis of schizophrenia and a research diagnosis of schizophrenia, established using the Item Group Checklist of the Schedule for Clinical Assessment in Neuropsychiatry, were enrolled. Antipsychotic subjective tolerability was rated by means of the Liverpool University Neuroleptic Side Effect Rating Scale. During the recruitment period, 245 men and 164 women with schizophrenia were recruited. In both sexes, the most frequently reported side effects were difficulty in concentrating, tiredness, and weight gain; these side effects occurred in approximately 50% of men and in up to 70% of women. Extrapyramidal and anticholinergic reactions were reported more often by women, whereas men reported sexual problems more often. After background group differences were controlled for, sex was the strongest determinant of the subjective tolerability of antipsychotic drugs. We therefore conclude that sex differences in the subjective tolerability of antipsychotic drugs should be taken into account in the pharmacological management of patients with schizophrenia. Studies should no longer consider men and women as a homogeneous group, given that the subjective tolerability of antipsychotic drugs substantially differs between sexes.     

Sex and age differences in the pharmacokinetics of alosetron

AIMS: To determine the effects of sex and age on the pharmacokinetics of alosetron. METHODS: Single oral and intravenous 2 mg doses of alosetron were administered on separate occasions to 48 healthy, young and elderly, males and females. Serum was sampled for 12 h post-dose to measure alosetron concentrations. RESULTS: Serum concentrations of alosetron were higher in females than in males, resulting from a sex difference in clearance by metabolism. Mean clearance values were 504 vs 677 ml min(-1) in young females vs males (mean ratio 0.75), and 461 vs 670 ml min(-1) in elderly females vs males (mean ratio 0.69). The sex difference in alosetron pharmacokinetics achieved statistical significance in the elderly, but not in the young. Irrespective of sex, alosetron clearance was increased by smoking. Serum concentrations tended to be higher in the elderly, although the effect of age was generally not significant. Volume of distribution was smaller in females (approximately 63 l) compared with males (approximately 84 l), regardless of age or the sex difference in body weight. CONCLUSIONS: A significant difference in clearance by metabolism of alosetron between the sexes, and possibly between the young and elderly was observed.     

Sex differences in dopamine release regulation in the striatum

The mesolimbic dopamine system—which originates in the ventral tegmental area and projects to the striatum—has been shown to be involved in the expression of sex-specific behavior and is thought to be a critical mediator of many psychiatric diseases. While substantial work has focused on sex differences in the anatomy of dopamine neurons and relative dopamine levels between males and females, an important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms independent of somatic activity. These processes can occur via homosynaptic mechanisms—such as presynaptic dopamine autoreceptors and dopamine transporters—as well as heterosynaptic mechanisms, such as retrograde signaling from postsynaptic cholinergic and GABAergic systems, among others. These regulators serve as potential targets for the expression of sex differences in dopamine regulation in both ovarian hormone-dependent and independent fashions. This review describes how sex differences in microcircuit regulatory mechanisms can alter dopamine dynamics between males and females. We then describe what is known about the hormonal mechanisms controlling/regulating these processes. Finally, we highlight the missing gaps in our knowledge of these systems in females. Together, a more comprehensive and mechanistic understanding of how sex differences in dopamine function manifest will be particularly important in developing evidence-based therapeutics that target this system and show efficacy in both sexes.Subject terms: Neurotransmitters, Reward