scholarly journals Lack of Male-Female Differences in Disposition and Esterase Hydrolysis of Ramipril to Ramiprilat in Healthy Volunteers after a Single Oral Dose

2003 ◽  
Vol 3 ◽  
pp. 1344-1358
Author(s):  
Tom B. Vree ◽  
Erik Dammers ◽  
Ivan Ulc ◽  
Stefan Horkovics-Kovats ◽  
Miroslav Ryska ◽  
...  
Keyword(s):  
Body Weight ◽  
Plasma Concentration ◽  
Active Metabolite ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Male And Female ◽  
Concentration Time ◽  
Males And Females ◽  
The Difference ◽  
Hydrolysis Of

The objective of this study was to identify differences in disposition and esterase hydrolysis of ramipril between male and female volunteers. Plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) data of ramipril and its active metabolite ramiprilat (-diacid) were obtained from a randomised, cross-over bioequivalence study in 36 subjects (18 females and 18 males). Participants received a single 5-mg oral dose of two different formulations of ramipril (Formulation I and II). Plasma ramipril and ramiprilat concentrations were determined according to validated methods involving liquid chromatography-mass spectrometry. A total number of 2 � 34 available plasma concentration-time curves of both the parent drug and the metabolite could be analysed, and variations (50�100% coefficient of variation [CV]) in plasma concentrations of both parent drug and metabolite were found. With both the formulations, the mean plasma concentrations-time curves of males and females were identical. The groups of female and male volunteers showed similar yields (AUCt = mg.h/L) of the metabolite ramiprilat (p = 0.37); however, females showed a higher AUCt/kg than males (p = 0.046). This difference was solely attributed to the difference in body weight between males and females (p = 0.00049). In both male and female groups, a subject-dependent yield of active metabolite ramiprilat was demonstrated, which was independent of the formulation.There is a large variation in the ramiprilat t1/2β(50�60% CV). There is a group of subjects who showed a t1/2βof approximately 80 h (15% CV), and two apparent groups with a longer t1/2βfor each formulation (124 h, 22.5% CV; 166 h, 21.6% CV, respectively, p = 0.0013). This variation in the terminal half-life of ramiprilat is not sex related. In all three groups of half-lives, the corresponding Cmax values (mean � SD) of ramiprilat in males and females were identical. Thus, with identical Cmaxand half-lives, the difference found in the AUCt/kg of ramiprilat must be due to the difference in dose, as the consequence of the difference in body weight, following a standard dose of 5 mg in both males and females.This study showed clearly that despite subject-dependent hydrolysis of ramipril to the active metabolite ramiprilat, the variability in the rate of hydrolysis between males and females is similar. With a fixed dose (5 mg), females received a higher dose/kg than males and consequently showed a higher AUCt/kg of the active metabolite ramiprilat.

Clinical Impact of Co-medication of Levetiracetam and Clobazam with Proton Pump Inhibitors: A Drug Interaction Study

2020 ◽  
Vol 21 (2) ◽  
pp. 126-131
Author(s):  
Bhuvanachandra Pasupuleti ◽  
Vamshikrishna Gone ◽  
Ravali Baddam ◽  
Raj Kumar Venisetty ◽  
Om Prakash Prasad
Keyword(s):  
Plasma Concentration ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Plasma Concentrations ◽  
Control Group ◽  
Drug Concentrations ◽  
Significant Difference ◽  
Post Hoc ◽  
Hydrolysis Of ◽  
Cytochrome P 450

Background: Clobazam (CLBZ) metabolized primarily by Cytochrome P-450 isoenzyme CYP3A4 than with CYP2C19, Whereas Levetiracetam (LEV) is metabolized by hydrolysis of the acetamide group. Few CYP enzymes are inhibited by Proton Pump Inhibitors (PPIs) Pantoprazole, Esomeprazole, and Rabeprazole in different extents that could affect drug concentrations in blood. The aim of the present study was to evaluate the effect of these PPIs on the plasma concentrations of LEV and CLBZ. Methods: Blood samples from 542 patients were included out of which 343 were male and 199 were female patients and were categorized as control and test. Plasma samples analyzed using an HPLC-UV method. Plasma concentrations were measured and compared to those treated and those not treated with PPIs. One way ANOVA and games Howell post hoc test used by SPSS 20 software. Results: CLBZ concentrations were significantly 10 folds higher in patients treated with Pantoprazole (P=0.000) and 07 folds higher in patients treated with Esmoprazole and Rabeprazole (P=0.00). Whereas plasma concentration of LEV control group has no statistical and significant difference when compared to pantoprazole (P=0.546) and with rabeprazole and esomeprazole was P=0.999. Conclusion: The effect of comedication with PPIs on the plasma concentration of clobazam is more pronounced for pantoprazole to a greater extent when compared to esomeprazole and rabeprazole. When pantoprazole is used in combination with clobazam, dose reduction of clobazam should be considered, or significance of PPIs is seen to avoid adverse effects.

scholarly journals Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions

2020 ◽  
Vol 37 (12) ◽  
Author(s):  
Hannah Britz ◽  
Nina Hanke ◽  
Mitchell E. Taub ◽  
Ting Wang ◽  
Bhagwat Prasad ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Organic Anion ◽  
Plasma Concentrations ◽  
Whole Body ◽  
Time Profiles ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Anion Transporter ◽  
Physiologically Based

Abstract Purpose To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling. Methods PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies. Results The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold. Conclusions Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.

scholarly journals Influence ofABCC2andABCC4Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

2015 ◽  
Vol 59 (6) ◽  
pp. 3240-3245 ◽  
Author(s):  
Kanokrat Rungtivasuwan ◽  
Anchalee Avihingsanon ◽  
Narukjaporn Thammajaruk ◽  
Siwaporn Mitruk ◽  
David M. Burger ◽  
...  
Keyword(s):  
Body Weight ◽  
Multivariate Analysis ◽  
Plasma Concentration ◽  
Protease Inhibitors ◽  
Demographic Data ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
The Mean

ABSTRACTTenofovir (TFV) is eliminated by renal excretion, which is mediated through multidrug-resistant protein 2 (MRP2) and MRP4, encoded byABCC2andABCC4, respectively. Genetic polymorphisms of these transporters may affect the plasma concentrations of tenofovir. Therefore, the aim of this study was to investigate the influence of genetic and nongenetic factors on tenofovir plasma concentrations. A cross-sectional study was performed in Thai HIV-infected patients aged ≥18 years who had been receiving tenofovir disoproxil fumarate at 300 mg once daily for at least 6 months. A middose tenofovir plasma concentration was obtained. Multivariate analysis was performed to investigate whether there was an association between tenofovir plasma concentrations and demographic data, including age, sex, body weight, estimated glomerular filtration rate (eGFR), hepatitis B virus coinfection, hepatitis C virus coinfection, duration of tenofovir treatment, concomitant use of ritonavir-boosted protease inhibitors, and polymorphisms ofABCC2andABCC4. A total of 150 Thai HIV-infected patients were included. The mean age of the patients was 43.9 ± 7.2 years. The mean tenofovir plasma concentration was 100.3 ± 52.7 ng/ml. In multivariate analysis, a low body weight, a low eGFR, the concomitant use of ritonavir-boosted protease inhibitors, and theABCC44131T → G variation (genotype TG or GG) were independently associated with higher tenofovir plasma concentrations. After adjusting for weight, eGFR, and the concomitant use of ritonavir-boosted protease inhibitors, a 30% increase in the mean tenofovir plasma concentration was observed in patients having theABCC44131 TG or GG genotype. Both genetic and nongenetic factors affect tenofovir plasma concentrations. These factors should be considered when adjusting tenofovir dosage regimens to ensure the efficacy and safety of a drug. (This study has been registered at ClinicalTrials.gov under registration no. NCT01138241.)

scholarly journals Suicide Notes: Exaggerations by Males and Females

2020 ◽  
Vol 1 (1) ◽  
pp. 1-10
Author(s):  
Purbo Kusumastuti ◽  
Aulia Apriana ◽  
Yazid Basthomi
Keyword(s):  
Gender Differences ◽  
Gender Stereotypes ◽  
Language Production ◽  
Positive Emotions ◽  
Negative Emotions ◽  
Male And Female ◽  
Suicide Notes ◽  
Males And Females ◽  
The Difference ◽  
Female Subjects

Touching into the gender differences between males and females in expressing the use of exaggeration expressions, this study analyzes the relevant data using the LIWC tool, the HIP method, and the deficit and difference theories. This study found that in relation to the gender stereotypes, both males and females speak differently, yet also demonstrate similarities. Both the male and female subjects express emotions equally in the language production; yet, the negative emotions are dominated by the males, and the positive emotions are dominated by the females. The difference of emotion productions influences the differences in the males’ production of exaggeration expressions, such as empty adjectives, italic expressions, and hyperbole by the female subjects.  

scholarly journals The correlation between dimensional characteristics, live weight and fluff and feather level of obroshynska gray and obroshynska white natural groups geese

2017 ◽  
Vol 19 (74) ◽  
Author(s):  
V. S. Zaplatynsky
Keyword(s):  
Body Weight ◽  
Linear Growth ◽  
Correlation Coefficients ◽  
Live Weight ◽  
Natural Group ◽  
Male And Female ◽  
Body Sizes ◽  
Males And Females ◽  
Natural Groups

This article presents data on dynamics of linear growth and weight rates of obroshynska gray and obroshynska gray natural groups geese, factional fluff content, correlation coefficients between body weight and body sizes and amount of feathers. It has been found that male and female individuals of obroshynska gray natural group geese dominated by live weight of obroshynska white natural group geese. Particularly, this advantage in 90 days aged males was 549.4 (P < 0.05), in 120 days aged males – 635.6 (P < 0.01) and in 180 days aged males – 422.6 (P < 0.05) g, in females – 177.0, 461.8 (P < 0.01) and 401.8 g respectively. It has been also revealed the obroshynska gray natural group geese domination by researched body sizes in all geese ages, but it was only reliable in some cases. Geese of both sexes in both natural groups were characterized by high fluff and feather level. We investigated age, sex and interbreed differentiation on fluff and feather levels in studied geese groups. It should be noted that fluff and feather level was better in white geese indicating a better fluff and feather quality. The correlation coefficients between body weight and overall fluff and feather levels in females of obroshynska gray natural group geese dependent on ages and fluff and feather levels were between -0.30 – +0.63, in males – between -0.51 – +0.68 and in obroshynska white natural groups geese coefficients were between -0.29 – +0.70 and -0.30 до +0.82 respectively. It has been found the correlations between geese body sizes and fluff and feather levels. In males and females geese from abroshynska gray natural group depenent on ages, body sizes and fluff and feather levels coefficients were -0.49 – +0.81 and -0.76 – +0.88, and for obroshynska white natural group geese – -0.49 – +0.90 and -0.65 – +0.65.

Exposure to Retinoic Acids in Non-Pregnant Women Following High Vitamin A Intake with a Liver Meal

2005 ◽  
Vol 75 (3) ◽  
pp. 187-194 ◽  
Author(s):  
Hartmann ◽  
Brørs ◽  
Bock ◽  
Blomhoff ◽  
Bausch ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Vitamin A ◽  
Safety Concern ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Pregnant Female ◽  
Time Curve ◽  
High Vitamin ◽  
Concentration Time ◽  
Plasma Concentration Time Curve

Animal liver is a rich source of vitamin A. Due to retinoic acid (RA) metabolites, vitamin A has a teratogenic potential and women are generally advised to avoid or to limit the consumption of liver during pregnancy. In a recent study in non-pregnant female volunteers following single and repeated doses of up to 30,000 IU/day of vitamin A as a supplement, the plasma concentration time curve of all-trans RA acid showed a diurnal-like profile. But, the overall exposure (AUC24h) remained essentially unaltered whereas AUC24h increased linearly with dose for 13-cis and 13-cis-4-oxo RA. The current study in non-pregnant female volunteers showed that a single high vitamin A intake with a liver meal (up to 120,000 IU) exhibited a similar diurnal-like plasma concentration time curve for all-trans RA and its overall exposure remained also unaltered, despite a temporary two-fold increase in peak plasma concentration. Concentrations of 13-cis and 13-cis-4-oxo RA increased several-fold after a liver meal, and exposure (AUC24h) increased three- to five-fold. Pooling our results with data in the literature revealed a linear relation between the mean AUC24h of 13-cis and 13-cis-4-oxo RA and vitamin A intake with liver. Metabolism to all-trans RA of vitamin A with liver seems not to be of safety concern. However, the observed increase of plasma concentrations and the dose-dependent increase in exposure to 13-cis and 13-cis-4-oxo RA support the current safety recommendations on vitamin A intake and suggest that women should be cautious regarding their consumption of liver-containing meals during pregnancy.

Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans.

1988 ◽  
Vol 6 (3) ◽  
pp. 517-526 ◽  
Author(s):  
K Mross ◽  
P Maessen ◽  
W J van der Vijgh ◽  
H Gall ◽  
E Boven ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Urinary Excretion ◽  
Half Life ◽  
Enterohepatic Circulation ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Volume Of Distribution ◽  
Maximum Plasma ◽  
Cumulative Urinary Excretion ◽  
Second Peak

Pharmacokinetics of doxorubicin (DOX), epidoxorubicin (EPI), and their metabolites in plasma have been performed in eight patients receiving 40 to 56 mg/m2 of both anthracyclines as a bolus injection in two sequential cycles. Terminal half-life and volume of distribution appeared to be smaller in case of EPI, whereas plasma clearance and cumulative urinary excretion was larger in comparison to DOX. The major metabolite of DOX was doxorubicinol (Aol) followed by 7-deoxy-doxorubicinol (7d-Aolon). Metabolism to glucuronides was found in case of EPI only. The area under the curves (AUC) of the metabolites of EPI decreased in the order of the glucoronides E-glu greater than Eol-glu, 7d-Aolon greater than epirubicinol (Eol). The AUC of Eol was half of the value in its counterpart Aol. In the case of EPI, the AUC of 7d-Aolon was twice the level of that of the corresponding metabolite of DOX. The terminal half-lives of the cytostatic metabolites Aol and Eol were similar, but longer than the corresponding values of their parent drugs. Half-lives of the glucuronides (E-glu, Eol-glu) were similar to the half-life of their parent drug. 7d-Aolon had a somewhat shorter half-life in comparison to both DOX and EPI. Approximately 6.2% of EPI and 5.9% of DOX were excreted by the kidney during the initial 48 hours. Aol was found in the urine of patients treated with DOX, whereas Eol, E-glu, and Eol-glu were detected in urine of patients treated with EPI. The cumulative urinary excretion appeared to be 10.5% for EPI and its metabolites, and 6.9% for DOX and its metabolite. The plasma concentration v time curves of (7d)-aglycones showed a second peak between two and 12 hours after injection, suggesting an enterohepatic circulation for metabolites lacking the daunosamine sugar moiety. The plasma concentrations of the glucuronides were maximal at 1.2 hours for E-glu and 1.9 hours for Eol-glu. All other compounds reached their maximum plasma concentration during the first minutes after the administration of DOX and EPI. Deviating plasma kinetics were observed in one patient, probably due to prior drug administration.

The reproductive cycle of the newt Triturus italicus

1992 ◽  
Vol 13 (2) ◽  
pp. 121-133 ◽  
Author(s):  
Fabio M. Guarino ◽  
Vincenzo Caputo ◽  
Francesco Angelini
Keyword(s):  
Body Weight ◽  
Reproductive Cycle ◽  
Annual Variation ◽  
Southern Italy ◽  
Fat Body ◽  
Reproductive Activity ◽  
Male And Female ◽  
Egg Deposition ◽  
Males And Females ◽  
Mountain Population

AbstractThis paper describes the reproductive cycle in male and female newts Triturus italicus (Peracca, 1898) from a mountain population living in southern Italy. The male shows a well-defined seasonal testicular cycle: spermatogenesis almost stops from November to March, resuming in April-May; the maturative stage of spermatogenesis occurs in summer and spermiohistogenesis is completed by late October. Spermiation starts in late autumn and culminates in the next spring. The female shows a seasonal ovarian cycle. Vitellogenesis starts in September; ovulation and egg deposition occur between late January and early June. Thus potentially long reproductive activity is demonstrated in both males and females of T italicus. Testicular and ovarian weights seem to be reliable indices of the reproductive status of an animal. Annual variation in gonadal weight appears unrelated to annual variation in fat body weight in both sexes.

scholarly journals Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

2009 ◽  
Vol 53 (10) ◽  
pp. 4407-4413 ◽  
Author(s):  
Déborah Hirt ◽  
Saik Urien ◽  
Mathieu Olivier ◽  
Hélène Peyrière ◽  
Boubacar Nacro ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Body Weight ◽  
Plasma Concentrations ◽  
Individual Characteristics ◽  
Population Pharmacokinetic ◽  
Ratio Test ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Immunodeficiency Virus

ABSTRACT We aimed in this study to describe efavirenz concentration-time courses in treatment-naïve children after once-daily administration to study the effects of age and body weight on efavirenz pharmacokinetics and to test relationships between doses, plasma concentrations, and efficacy. For this purpose, efavirenz concentrations in 48 children were measured after 2 weeks of didanosine-lamivudine-efavirenz treatment, and samples were available for 9/48 children between months 2 and 5 of treatment. Efavirenz concentrations in 200 plasma specimens were measured using a validated high-performance liquid chromatography method. A population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. The estimated minimal and maximal concentrations of efavirenz in plasma (C min and C max, respectively) and the area under the concentration-time curve (AUC) were correlated to the decrease in human immunodeficiency virus type 1 RNA levels after 3 months of treatment. The threshold C min (and AUC) that improved efficacy was determined. The target minimal concentration of 4 mg/liter was considered for toxicity. An optimized dosing schedule that would place the highest percentage of children in the interval of effective and nontoxic concentrations was simulated. The pharmacokinetics of efavirenz was best described by a one-compartment model with first-order absorption and elimination. The mean apparent clearance and volume of distribution for efavirenz were 0.211 liter/h/kg and 4.48 liters/kg, respectively. Clearance decreased significantly with age. When the recommended doses were given to 46 of the 48 children, 19% (44% of children weighing less than 15 kg) had C mins below 1 mg/liter. A significantly higher percentage of children with C mins of >1.1 mg/liter or AUCs of >51 mg/liter·h than of children with lower values had viral load decreases greater than 2 log10 copies/ml after 3 months of treatment. Therefore, to optimize the percentage of children with C mins between 1.1 and 4 mg/liter, children should receive the following once-daily efavirenz doses: 25 mg/kg of body weight from 2 to 6 years, 15 mg/kg from 6 to 10 years, and 10 mg/kg from 10 to 15 years. These assumptions should be prospectively confirmed.

Social influences on female athletic performance

1976 ◽  
Vol 8 (2) ◽  
pp. 123-129 ◽  
Author(s):  
K. F Dyer
Keyword(s):  
Social Factors ◽  
Athletic Performance ◽  
Social Influences ◽  
World Record ◽  
Male And Female ◽  
Female Performance ◽  
Males And Females ◽  
The Difference ◽  
World Records

The differences between male and female performance in athletic track events at which both compete are compared. It is found that the difference between male and female performance as measured by world records is declining in all events and declining most rapidly in those events in which the differences at the present time are largest. Analysis of national track records for these same events shows considerable differences between different countries in average male/female differentials and the differences between males and females for some events in some countries is much smaller than world record differences.It is concluded that social factors such as differing degrees of encouragement and differing levels of expectation are important factors in limiting female athletic performance.

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