Sex-related Differences In Pharmacokinetics Research Articles

Sex-related pharmacokinetic differences and mechanisms of metapristone (RU486 metabolite)

Metapristone is the primary metabolite of the abortifacient mifepristone (RU486), and is being developed as a safe and effective cancer metastatic chemopreventive agent for both sexes. Here, we systematically investigated the sex-related pharmacokinetics of metapristone in both rats and dogs, and explored the related mechanisms of actions. Administration of metapristone to rats and dogs showed that plasma concentrations of metapristone (AUC, Cmax) were significantly higher in female dogs and rats than in males. The sex-related differences in pharmacokinetics become more significant after ten consecutive days of oral administration. Female liver microsomes metabolized metapristone significantly slower than the male ones. The results from P450 reaction phenotyping using recombinant cDNA-expressed human CYPs in conjunction with specific CYP inhibitors suggested that CYP1A2 and CYP3A4 are the predominant CYPs involved in the metapristone metabolism, which were further confirmed by the enhanced protein levels of CYP1A2 and CYP3A4 induced by 1-week oral administration of metapristone to rats. The highest tissue concentration of metapristone was found in the liver. The study demonstrates, for the first time, the sex-related pharmacokinetics of metapristone, and reveals that activities of liver microsomal CYP1A2 and CYP3A4 as well as the renal clearance are primarily responsible for the sex-related pharmacokinetics.

Gender medicine: a task for the third millennium

Gender-specific medicine is the study of how diseases differ between men and women in terms of prevention, clinical signs, therapeutic approach, prognosis, psychological and social impact. It is a neglected dimension of medicine. In this review we like to point out some major issues in five enormous fields of medicine: cardiovascular diseases (CVDs), pharmacology, oncology, liver diseases and osteoporosis. CVDs have been studied in the last decades mainly in men, but they are the first cause of mortality and disability in women. Risk factors for CVD have different impacts in men and women; clinical manifestations of CVD and the influence of drugs on CVD have lot of gender differences. Sex-related differences in pharmacokinetics and pharmacodynamics are also emerging. These differences have obvious relevance to the efficacy and side effect profiles of various medications in the two sexes. This evidence should be considered for drug development as well as before starting any therapy. Gender disparity in cancer incidence, aggressiveness and prognosis has been observed for a variety of cancers and, even if partially known, is underestimated in clinical practice for the treatment of the major types of cancer. It is necessary to systematize and encode all the known data for each type of tumor on gender differences, to identify where this variable has to be considered for the purposes of the prognosis, the choice of treatment and possible toxicity. Clinical data suggest that men and women exhibit differences regarding the epidemiology and the progression of certain liver diseases, i.e., autoimmune conditions, genetic hemochromatosis, non-alcoholic steatohepatitis and chronic hepatitis C. Numerous hypotheses have been formulated to justify this sex imbalance including sex hormones, reproductive and genetic factors. Nevertheless, none of these hypothesis has thus far gathered enough convincing evidence and in most cases the evidence is conflicting. Osteoporosis is an important public health problem both in women and men. On the whole, far more epidemiologic, diagnostic and therapeutic studies have been carried out in women than in men. In clinical practice, if this disease remains underestimated in women, patients' and physicians' awareness is even lower for male osteoporosis, for which diagnostic and therapeutic strategies are at present less defined. In conclusion this review emphasizes the urgency of basic science and clinical research to increase our understanding of the gender differences of diseases.

Pharmacokinetics and Safety of Ezetimibe/Simvastatin Combination Tablet

Ezetimibe/simvastatin combination tablet has been approved for the treatment of high low-density lipoprotein cholesterol (LDL-C) levels in patients with primary hypercholesterolaemia or mixed hypercholesterolaemia as adjunctive therapy to diet, when diet alone is insufficient in lowering cholesterol. The aims of this study were to assess the pharmacokinetics and safety of an ezetimibe/simvastatin combination tablet after oral single-dose administration in healthy Chinese subjects including sex-related differences in pharmacokinetics. This was an open-label, single-dose study. Twelve healthy subjects (six males and six females) received a single dose of an ezetimibe/simvastatin combination tablet (ezetimibe 10mg and simvastatin 40mg). The pharmacokinetic parameters for ezetimibe and simvastatin were assessed by determining total ezetimibe, free ezetimibe, simvastatin and simvastatin acid concentrations using a validated liquid chromatography-tandem mass spectrometry method. Safety was evaluated by monitoring adverse events, laboratory assays, vital signs, physical examinations and 12-lead electrocardiograms. The pharmacokinetic parameters (mean±SD) for total ezetimibe and free ezetimibe following a single dose were: maximum plasma drug concentration (C(max)) 81.56±26.62 and 9.40±6.17ng/mL; time to reach C(max) (t(max)) 0.93±0.30 and 1.25±1.27h; elimination half-life (t(½)) 24.32±13.27 and 18.90±9.66h, and mean area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(last)) 579.06±241.45 and 126.01±69.01ng·h/mL, respectively. The pharmacokinetic parameters (mean±SD) for simvastatin and simvastatin acid following a single dose were: C(max) 11.92±5.50 and 3.37±1.78ng/mL, t(max) 0.98±0.28 and 3.73±1.68h, t(½) 4.19±1.81 and 7.65±7.96h, and mean AUC(last) 33.63±20.41 and 32.50±18.79ng·h/mL. Higher AUC(last) and AUC from time zero to infinity (AUC(∞)), and lower apparent total body clearance of drug from plasma after oral administration (CL/F) for total ezetimibe and free ezetimibe were observed in female subjects compared with those in male subjects. There were no differences between the pharmacokinetic parameters of simvastatin and simvastatin acid for female and male subjects in the study. Ezetimibe/simvastatin combination tablet has a generally favourable safety and tolerability profile in healthy Chinese subjects. A statistically significant difference with regard to sex in the pharmacokinetics of ezetimibe was observed. Sex had no effect on the pharmacokinetics of simvastatin and simvastatin acid.

Sex-related differences in pharmacokinetics and pharmacodynamics of anti-hypertensive drugs

Sex-specific differences in pharmacokinetics and pharmacodynamics have been reported to have important clinical consequences. In this review, some representative sex-specific differences in absorption and transporters (that is, P-glycoprotein (P-gp)), metabolic processes (that is, those that involve cytochrome P450 (CYP)), clearance (Cl) processes (for example, renal excretion or other pharmacokinetic parameters) and involvement of sex hormones (that is, estrogen and testosterone) in the regulation of some metabolic enzymes are introduced for each of the following categories of anti-hypertensive drugs: calcium-channel blockers, angiotensin-receptor blockers and angiotensin-converting enzyme inhibitors, diuretic agents, and β-adrenergic-receptor blockers (β-blockers). In many cases, female sex is a risk factor for adverse effects or attenuated clinical responses because of lower Cl, smaller distribution volumes, higher activity of some metabolic enzymes (especially hepatic CYP3A4), or presence of sex hormones. Additionally, some of these factors often co-contribute to the sex-specific differences. Furthermore, pharmacodynamic variability among individuals is often larger than pharmacokinetic variability; in other words, it could become a predominant determinant of interindividual differences in therapeutic responses. Thus, studies of sex-specific differences in pharmacokinetics and pharmacodynamics should be conducted. However, sex-related disparities in pharmacokinetics may not necessarily correspond to clinically significant differences in therapeutic response. There are still large gaps in our knowledge of sex-specific differences in clinical pharmacology and much more research is needed.

Patterns of chemotherapy‐induced toxicities in younger children and adolescents with rhabdomyosarcoma

Patients aged >10 years with rhabdomyosarcoma have an inferior outcome compared with patients ages 1 to 9 years, which may be explained by toxicities (adverse events [AEs]) that result in chemotherapy dose reductions. AEs observed during 1 of 3 randomized chemotherapy regimens (vincristine, dactinomycin, and cyclophosphamide [VAC]; vincristine, dactinomycin, and ifosfamide [VAI]; or vincristine, ifosfamide, and etoposide [VIE]) in the Fourth Intergroup Rhabdomyosarcoma Study were recorded. The incidence of toxicities by age and treatment regimen was determined. The odds of developing AEs in a particular age group (ages 5-9 years, 10-14 years, and 15-20 years) were compared with the odds in the control group of patients ages 1 to 4 years. In total, 657 patients were eligible for analysis. The estimated 5-year event-free survival rates were 78%, 83%, 67%, and 58% for the groups ages 1 to 4 years, 5 to 9 years, 10 to 14 years, and 15 to 20 years, respectively. Patients ages 15 to 20 years experienced less neutropenia (odds ratio [OR], 0.43; P < .0001), thrombocytopenia (OR, 0.41; P < .0001), anemia (OR, 0.34; P < .0001), and infection (OR, 0.41; P < .0001) compared with younger patients, although they received similar amounts of chemotherapy. In contrast, peripheral nervous system toxicity was higher in adolescents aged >10 years (OR, 4.18; P < .0001). Females experienced more neutropenia (OR, 1.28; P = .05) and thrombocytopenia (OR, 1.26; P = .06) compared with males. Adolescents who received treatment for rhabdomyosarcoma experienced significantly less hematologic toxicity and more peripheral nervous system toxicity compared with younger children despite receiving similar amounts of chemotherapy. Although outcomes were inferior in adolescents, it was unclear whether the differences in toxicity observed in the current study had an impact on outcome. The authors concluded that future studies examining the age-related and sex-related differences in pharmacokinetics of chemotherapy are necessary.

The Current State of Knowledge on Age, Sex, and Their Interactions on Clinical Pharmacology

Pharmacokinetic and pharmacodynamic changes occur with increasing age. Sex differences in pharmacokinetics and pharmacodynamics exist and persist at older age. The issue for the clinician is how to best treat the older patient with currently available knowledge. This communication highlights age- and sex-related differences in pharmacokinetics that should influence clinical practice and prescribing guidelines to optimize clinical responses. The most compelling data for sex-specific medication dosing guidelines for older patients are related to volume of distribution differences, or size differences, between the sexes and to differences in glomerular filtration rates.

Safety, Tolerability, and Pharmacokinetics of PTC124, a Nonaminoglycoside Nonsense Mutation Suppressor, Following Single‐ and Multiple‐Dose Administration to Healthy Male and Female Adult Volunteers

Nonsense (premature stop codon) mutations are causative in 5% to 15% of patients with monogenetic inherited disorders. PTC124, a 284-Dalton 1,2,4-oxadiazole, promotes ribosomal readthrough of premature stop codons in mRNA and offers therapeutic potential for multiple genetic diseases. The authors conducted 2 phase I studies of PTC124 in 62 healthy adult volunteers. The initial, single-dose study evaluated doses of 3 to 200 mg/kg and assessed fed-fasting status on pharmacokinetics following a dose of 50 mg/kg. The subsequent multiple-dose study evaluated doses from 10 to 50 mg/kg/dose twice per day (bid) for up to 14 days. PTC124 administered orally as a liquid suspension was palatable and well tolerated through single doses of 100 mg/kg. At 150 and 200 mg/kg, PTC124 induced mild headache, dizziness, and gastrointestinal events. With repeated doses through 50 mg/kg/dose bid, reversible transaminase elevations <2 times the upper limit of normal were sometimes observed. Immunoblot analyses of peripheral blood mononuclear cell extracts revealed no protein elongation due to nonspecific ribosomal readthrough of normal stop codons. PTC124 plasma concentrations exceeding the 2- to 10-microg/mL values associated with activity in preclinical genetic disease models were safely achieved. No sex-related differences in pharmacokinetics were seen. No drug accumulation with repeated dosing was apparent. Diurnal variation was observed, with greater PTC124 exposures after evening doses. PTC124 excretion in the urine was <2%. PTC124 pharmacokinetics were described by a 1-compartment model. Collectively, the data support initiation of phase II studies of PTC124 in patients with nonsense mutation-mediated cystic fibrosis and Duchenne muscular dystrophy.

Gender and Its Effect in Cardiovascular Pharmacotherapeutics: Recent Considerations

Gender differences in drug pharmacokinetics and pharmacodynamics have been recognized for some time. This issue has generally been ignored in clinical practice, despite there being ample evidence to suggest that gender can influence multiple aspects of pharmacokinetics. Gastric acid secretion, gastrointestinal blood flow, proportions of muscular and adipose tissue, the amount of drug-binding proteins, gender-specific changes in the available amount of P450 isozymes, physiologic and hormonal changes during the menstrual cycle, and differences in renal blood flow are several factors that may have some bearing on sex-related differences in pharmacokinetics. Furthermore, female-specific issues such as pregnancy, menopause, oral contraceptive use, and menstruation may independently influence drug metabolism and serve as confounders to the interpretation of gender differences in drug handling or effect. While gender-related pharmacodynamic data are limited, evidence suggests that women are more prone to the development of torsade de pointes from proarrhythmic drugs such as quinidine or d-sotalol and have an increased cardiovascular risk with the use of digoxin. The specific risk:benefit ratio for individual cardiovascular medications should be more routinely considered in the context of gender.

Influence of sex on the pharmacokinetics of tolmetin in the rat

The purpose of this study was to investigate sex-related differences in the pharmacokinetics of tolmetin, a potent nonsteroidal anti-inflammatory drug, in the rat. Male and female Wistar rats received oral tolmetin at two dose levels, 3.2 and 10 mg/kg. Blood samples were drawn at selected times after drug administration, and tolmetin concentration in whole blood was determined. Tolmetin was rapidly absorbed in all cases. C max increased with the dose, but was similar in both sexes. Notwithstanding, tolmetin half-life was significantly prolonged in females compared with males. As a result of the prolonged half-life, area under the curve values were significantly higher in females than in males. Tolmetin clearance was significantly reduced in females. The present results strongly suggest sex-related differences in the pharmacokinetics of tolmetin in the rat. Tolmetin elimination appears to be impaired in females, compared with males. The existence of sex-related differences in tolmetin pharmacokinetics in other species, including humans, requires further investigation.

Gender differences in human pharmacokinetics and pharmacodynamics

Gender differences in pharmacokinetics and pharmacodynamics have long been recognized in animals. In humans, however, little attention has been paid to this field despite at least theoretical reasons to believe that gender may be an important variable in the processes of absorption, distribution, metabolism, and excretion. Gastric acid secretion, gastrointestinal blood flow, proportions of muscular and adipose tissue, amount of drug binding proteins, gender-specific cytochrome P450 isozymes, physiologic and hormonal changes during the menstrual cycle, and renal blood flow are several factors that may contribute to sex-related differences in pharmacokinetics. Clinical investigations have documented greater absorption and subsequent incorporation of iron into erythrocytes, and higher bioavailability of ethanol in females. Women have been shown to have a slower metabolism of mephobarbital and propranolol but an increased biotransformation of methylprednisolone, all three of which are metabolized by enzymes of the cytochrome P450 system. Lastly, the renal excretion of amantadine was inhibited significantly by quinidine and quinine in men but not in women. While gender-specific pharmacodynamic data are meager, evidence also supports the existence of sex-related differences. Women appear to be more prone to develop torsades de points from drugs such as quinidine and procainamide than men. A dimorphism in insulin sensitivity has been demonstrated with males having an enhanced response compared to females. Pharmacokinetic and pharmacodynamic sex-related differences exist and are complex. Future research efforts should be designed to provide more gender-specific information on drug disposition and clinical effect.

The sex-related differences in aspirin pharmacokinetics in rabbits and man and its relationship to antiplatelet effects

There are a number of reports which suggest that the antithrombotic effect of aspirin is limited to males. It is unclear whether this effect is due to sex-related differences in the effect of aspirin on platelets, the vessel wall, or the pharmacokinetics of aspirin. To test these possibilities we examined the sex-related differences in (1) vessel wall PGI 2 release and its inhibition by and recovery from aspirin in rabbits; (2) the effects of aspirin on platelet aggregation, thromboxane B 2 and beta-thromboglobulin (BTG) release in man, and (3) the pharmacokinetic characteristics of aspirin, in both rabbits and man. Vascular wall PGI 2 measured as 6-keto-PGF 1α, was not different in male and females rabbits, and was inhibited to a similar extent by identical concentrations of aspirin. The duration of this inhibitory effect was also the same in males and females. The pattern of inhibition of collagen-induced platelet aggregation, and collagen-induced thromboxane B 2 and BTG release by aspirin were not different in either sex. There was, however, a sex-related difference in a number of pharmacokinetic characteristics of aspirin both in rabbits and man. Thus, aspirin was absorbed more rapidly, distributed in larger apparent volume and was hydrolysed more rapidly in females. These observations suggest that the sex-related differences in the antithrombotic effects of aspirin seen in clinical studies are not due to differences in the effects of aspirin on the inhibition of platelet function mediated by the inhibition of cyclo-oxygenase in either the platelet or the vessel wall. An effect of aspirin on platelet function independent of the inhibition of cyclo-oxygenase has been described and it is possible that this effect may be influenced by sex-related differences in the pharmacokinetics of aspirin.