Sex Differences In Elimination Research Articles

Sex Differences in the Pharmacokinetics of Cannabidiol and Metabolites Following Oral Administration of a Cannabidiol-Dominant Cannabis Oil in Healthy Adults.

Introduction: Oral cannabidiol (CBD) product use is increasingly growing among women; however, there is a lack of data on sex differences in the pharmacokinetics (PKs) of CBD and its primary metabolites, 7-hydroxy-CBD (7-OH-CBD) and 7-carboxy-CBD (7-COOH-CBD), after repeated doses. Materials and Methods: The present study is a secondary analysis of data from a randomized, double-blind, placebo-controlled multiple-dose trial of a commercially available, CBD-dominant oral cannabis product. Healthy participants (n=17 males and 15 females) were randomized to receive 120 to 480 mg of CBD daily for 7 days. Dosing groups were pooled for all analyses due to sample size limitations. Analyses compared plasma PK parameters by sex, day, and sex×day. Results: For raw PK parameters for CBD and metabolites, there were no statistically significant effects of sex×day or sex (all p-values >0.05). For metabolite-to-parent ratios (MPRs) of AUC0-t, there were significant effects of the sex×day interactions for 7-OH-CBD (F=6.89, p=0.016) and 7-COOH-CBD (F=5.96, p=0.021). For 7-OH-CBD, follow-up analyses showed significant simple effects of day within females (t=4.13, p<0.001), but not within males (t=0.34, p=0.73), such that 7-OH-CBD MPRs increased significantly from day 1 to 7 for females, but not for males. For 7-COOH-CBD, follow-up analyses revealed significant simple effects of day within females (t=8.24, p<0.001) and males (t=5.20, p<0.001), therefore 7-COOH-CBD MPRs increased significantly from day 1 to 7 in both sexes, but the increase was significantly greater among females than among males. Within dosing days, there were no statistically significant simple effects of sex on MPRs of 7-OH-CBD or 7-COOH-CBD. Conclusions: Females exhibited greater relative exposure to CBD metabolites in plasma over time, which may reflect sex differences in CBD metabolism or elimination. Further research assessing the safety implications of higher relative exposure to CBD metabolites over longer periods of time is warranted to mirror typical consumer use patterns.

Enhanced elimination of perfluorooctane sulfonic acid by menstruating women: evidence from population-based pharmacokinetic modeling.

Human biomonitoring studies have shown that concentrations of perfluorooctane sulfonic acid (PFOS) in men are higher than in women. We investigate sex differences in elimination of PFOS by fitting a population-based pharmacokinetic model to six cross-sectional data sets from 1999 to 2012 from the US National Health and Nutrition Examination Survey (NHANES) and derive human first-order elimination rate constants (kE) and corresponding elimination half-lives (t1/2) for PFOS, where t1/2 = ln 2/kE. We use a modified version of the Ritter population-based pharmacokinetic model and derive elimination rate constants separately for men and women. The model accounts for population-average lifetime changes in PFOS intake, body weight, and menstruation rate. We compare the model-derived elimination rate constant for hypothetical nonmenstruating women to the elimination rate constant for men and women when menstruation is included as a loss process to evaluate the hypothesis that loss of PFOS by menstruation is an important process for women. The modeled elimination half-life for men is 4.7 years, and the modeled elimination half-life for women when excluding losses from menstruation is 3.7 years. The elimination half-life for women when menstruation is included in the model is 4.0 years. Thus, menstruation accounts for 30% of the discrepancy in elimination of PFOS between men and women. The remaining discrepancy is likely due to other sex-specific elimination routes that are not considered in our modeling.

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 the Uptake and Disposition of Perfluorooctanoic Acid in Fathead Minnows after Oral Dosing

Perfluorooctanoic acid (PFOA) among other perfluorinated acids is becoming recognized as a ubiquitous environmental contaminant. PFOA is resistant to environmental degradation and appears to undergo no biotransformation in animals. Previous toxicokinetic studies in rodents have indicated that urinary excretion is the most important elimination pathway once PFOA has been absorbed. In some species such as rats, large sex-related differences in urinary excretion have been reported, with females having a much shorter blood or plasma elimination half-life than that of males. It is unknown whether this phenomenon occurs in fish. Therefore, this study determined the disposition of PFOA in male and female fathead minnows (Pimephales promelas) after a single oral dose of PFOA. After dosing, minnows were subsequently euthanized at various times until 336 h postdosing and the PFOA concentration was measured in plasma, gonads, and fish carcass. The concentration-time profiles of PFOA were then analyzed using toxicokinetic methods. The results indicated a clear sex difference in the elimination of PFOA. The plasma elimination half-life of PFOA in female minnows was 6.3 h while in male minnows it was 68.5 h. Pretreatment of female minnows with the synthetic androgen trenbolone substantially delayed the elimination of PFOA, causing the elimination half-life to increase to 25.3 h. In males, pretreatment with the synthetic estrogen ethynylestradiol (EE2) had little effect on PFOA toxicokinetics. These results indicate that the sex differences in PFOA elimination in fathead minnows can at least partially be modulated by exposure to synthetic sex steroids. Whether sex differences in PFOA elimination in minnows is attributable to differences in renal transport activity, as it appears to be for rodents, is unknown at present but clearly warrants further study.

Single administration toxicokinetic studies of decalin (decahydronaphthalene) in rats and mice.

Decalin (decahydronaphthalene) is an industrial solvent known to cause alpha2u-globulin nephropathy in male rats. Studies were conducted using decalin (mixture of cis and trans isomers) to (1) characterize systemic elimination of decalin in rats and mice and (2) evaluate disposition of decalin, its metabolites, and kidney alpha2u-globulin in young and old rats of both sexes following a single 6-h whole-body inhalation exposure at up to 400 ppm decalin. Additionally, a separate group of young male F344/N rats were administered either cis- or trans-decalin iv at doses up to 20 mg/kg to assess disposition of each isomer, its metabolites, and kidney alpha2u-globulin. Decalin was eliminated from blood in a dose-dependent manner, regardless of sex, age, or species. C0 and AUC infinity increased supra-proportionally with exposure concentration. Mice were more efficient in eliminating decalin than rats at lower exposure concentrations, but nonlinear elimination kinetics were more noticeable at 400 ppm. Sex differences in blood decalin elimination were observed in rats; females had a consistently higher AUC infinity at all exposure concentrations. There was a dose-dependent increase in kidney decalin, decalone, and alpha2u-globulin in male rats exposed to decalin. Kidney alpha2u-globulin and decalone concentrations in old male rats were substantially lower than those in young males, but were similar to those observed in all (young and old) females. Compared to old males and all females, young male rats had significantly lower urinary decalol concentrations, but higher kidney decalin, decalone, and alpha2u-globulin concentrations. Administration of decalin to male rats as either the cis or trans isomer revealed that more cis -decalone is produced per unit dose as compared to trans-decalone, and that more trans-decalin accumulated in the kidney (as alpha2u-globulin-ligand complexes) compared to cis-decalin. These patterns of isomer-specific metabolism were also reflected in the cis/trans ratios of decalin in blood, as well as urinary decalol metabolites. The ratio of alpha2u-globulin to the total amount of decalin plus decalone measured in the male rat kidney was approximately 1.0. Therefore, alpha2u-globulin was a key factor in the accumulation of decalin and decalone in kidneys of young male rats, decalin and decalone were practically absent in all females and in old males.

Gender-related differences in pharmacokinetics and their clinical significance.

In this review I have attempted to summarize gender differences in pharmacokinetics involving the cytochrome P450 (CYP) isozymes of young and mature adults, excluding the effects of the menstrual cycle, use of oral contraceptives and pregnancy. Sex differences in drug metabolism and elimination are mainly related to steroid hormone levels. CYP3A4, responsible for the metabolism of over 50% of therapeutic drugs, exhibits higher activity in women than in men. Nonetheless, the absence of a sex difference has been reported by some workers. The activity of several other CYP (CYP2C19, CYP2D6, CYP2E1) isozymes and the conjugation (glucuronidation) activity involved in drug metabolism may be higher in men than in women. Drug metabolism in women is affected by sex-specific factors (menopause, pregnancy and menstruation) in addition to the cigarette smoking, drug ingestion and alcohol consumption that are more commonly observed factors in men. Furthermore, they are affected by physiological factors such as drug absorption, protein binding and elimination. Thus, careful attention should be paid to the side-effects and toxicity arising from sex differences in drug metabolism in clinical situations. Although there are specific ethical considerations regarding carrying out drug trials in women, the relationship between the side-effects and toxicity that may be influenced by hormones during drug metabolism and drug treatment needs further study.

Sex differences in dopamine receptor overproduction and elimination.

Density of dopamine D1 and D2 family receptors was assessed using autoradiography in male and female rats from 25 to 120 days of age, focusing on transitions through puberty into full adulthood. Males had greater overproduction (approximately 4.6-fold) and elimination of striatal D1 and D2 receptors than females, though their adult densities were very similar. Males had more extensive overproduction of D1 receptors in nucleus accumbens and sustained a greater density into adulthood (57.8 +/- 21.2%). These results have implications for understanding gender differences in the prevalence of clinical disorders associated with dopamine.

Concomitant toxicokinetics: techniques for and interpretation of exposure data obtained during the conduct of toxicology studies.

Toxicokinetic analyses have become a routine component of preclinical toxicology studies with pharmaceutical candidates. Evaluation of plasma and/or tissue samples from animals used in toxicology studies (or concurrent satellite groups) provides information on dose proportionality, the potential for dose accumulation, and the sex and species differences in distribution and elimination. Toxicokinetic information is used by toxicologists, toxicology management, clinicians, institutional review boards, regulatory agencies to ensure that exposure has occurred in animal species to a sufficient extent to minimize the potential risk of toxicities in humans. The requirements for descriptive toxicokinetics change depending on the stage of development of new drug candidates. Early in development, documentation of exposure in 1 species and sex of laboratory animal might be enough to justify preliminary development costs and initiation of product development. Later in development, it becomes necessary to know how new drug candidates are distributed and eliminated following subchronic and chronic administration in multiple species and both sexes. Finally, knowledge of toxicokinetics is used to help establish doses in long-term oncogenicity studies. Scientific, public, and regulatory pressures have recently dictated that the number of animals used in toxicology studies be closely monitored and minimized. Toxicokinetic evaluation of new drug candidates by a staggered sampling design is now routinely performed in our laboratories to maximize information obtained while reducing animal use.

Species- and sex-related differences in the plasma clearance and metabolite formation of antipyrine. A comparative study in four animal species: Cattle, goat, rat and rabbit

1. The plasma disposition of antipyrine, and its urinary metabolite pattern, were studied in both sexes of four animal species: rat, dwarf goat, rabbit and cattle. 2. No sex differences in plasma elimination of antipyrine were found in rabbit and goat; however, in rat and cattle the effect of sex was marked. As expected, male rat showed a higher plasma clearance value than female. In contrast bulls showed a significantly lower clearance value than cows. 3. Metabolite patterns varied widely from one species to another. The major urinary metabolite in rabbit and the two ruminant species was 4-hydroxy-antipyrine (OHA), whereas in rat 3-hydroxymethylantipyrine (HMA) was quantitatively the most important metabolite. 4. HMA was excreted in the 24 h urine in larger amounts by male rats than by females. Metabolism of antipyrine to HMA was also sexually different in the dwarf goat, but in this species females were more active than males. The effect of sex on the metabolite pattern in cattle was marked. 5. It is concluded that in ruminants there may be xenobiotic metabolic pathways which are under hormonal control, just as there are in rats and mice. If hormones influence drug metabolism in food-producing animals, residue levels of xenobiotics or their metabolites in food from animal origin may differ with the sex of the animal, or may be altered after treatment with anabolic hormones.

Kinetics of five benzodiazepine hypnotics in healthy subjects

Kinetics of five benzodiazepine hypnotics (15 mg flurazepam, 1 mg flunitrazepam, 5 mg nitrazepam, 10 mg temazepam, and 0.5 mg triazolam) were compared in the same group of 12 healthy subjects. Plasma concentrations of parent drugs were determined by capillary gas chromatography with electron-capture detection. For flurazepam, the N-desalkyl metabolite (DAF) was measured. Flunitrazepam, nitrazepam, temazepam, and triazolam were rapidly absorbed, although there was considerable variability; mean peak times (ranges) were: 1.3 (0.3 to 3) hr, 1.8 (0.7 to 6) hr, 1.2 (0.3 to 4) hr, and 1.1 (0.7 to 2) hr. Plasma concentrations of DAF increased rather slowly and reached their maximum between 3 and 48 hr after flurazepam. There were considerable differences in elimination t1/2s, with means of 35 (15 to 66) hr for flunitrazepam, 28 (22 to 33) hr for nitrazepam, 12 (8 to 22) hr for temazepam, 2.4 (1.4 to 3.9) hr for triazolam, and 84 (40 to 114) hr for DAF. Sex differences in elimination t1/2 were only observed for DAF: 99 hr in women and 69 hr in men. Our results show that there are considerable differences in the kinetics of the diazepines.

Disposition of zinc pyrithione in the rat

The pharmacokinetic profile of orally administered [2,6- 14C]-labelled zinc pyrithione (ZPT) was defined in male and female rats and was used to predict the blood concentrations of 14C at steady state correlating with the skeletal-muscle weakness observed in long-term feeding tests and mechanism studies. The 14C concentration was determined in blood, urine and faeces as a function of time following oral administration of doses of 0·5, 1·25 and 12·5 mg [ 14C]ZPT/kg. The major route of elimination from the body was the urine, in which all the ZPT appeared as metabolites. Mass-spectroscopic analysis of the urine indicated that a minor metabolite was 2-mercaptopyridine- N-oxide and the major metabolites were S-glucuronides of 2-mercaptopyridine- N-oxide. Radioassay of tissues indicated that ZPT was rapidly excreted and was not retained in the body to any significant degree. A two-compartment open model was used to describe the dynamics of ZPT in males and females given 0·5, 1·25 or 12·5 mg/kg. Kinetic constants for the same dose indicated sex differences in plasma elimination, renal clearance, time required for attainment of maximum blood concentration and rate of absorption. The ratio for 14C binding in red blood cells and plasma, respectively, was 5:1 at 96 hr and increased to ⩾ 45:1 at 240 hr, a probable reason for the low renal clearance rates. No sex difference in the concentration of 14C in blood at steady-state levels (maximum and minimum) was seen with the 0·5 mg/kg dose, but a significant difference was apparent at 1·25 mg/kg, the concentration being higher in the females. The significantly lower blood concentration of 14C in the males, in conjunction with the apparent higher rate of metabolism in the male, provide a reasonable explanation for the demonstrated sex difference in the dietary level of ZPT capable of producing an effect.