Gender differences in concentration of itraconazole and hydroxyitraconazole

Introduction: Itraconazole is an antifungal drug belonging to the triazole group. After oral application, it is rapidly absorbed, but its bioavailability is reduced due to an intensive first-pass through the liver metabolism effect. A large number of metabolites (the most important of which is hydroxyitraconazole) are produced by isoform CYP3A4 of cytochrome P450. The variability of itraconazole pharmacokinetics is the result of numerous factors that have not yet been fully clarified. Our study aimed to investigate the influence of gender on itraconazole and hydroxyitraconazole plasma concentrations in healthy adults after an oral application of a single dose of itraconazole. Methods: Pharmacokinetic analysis was performed after oral administration of itraconazole in a single dose of 100 mg to 22 male and 16 female healthy volunteers. Blood samples were collected before taking the drug and at appropriate time intervals up to 72 hours later. Itraconazole and hydroxyitraconazole concentrations were determined using a validated liquid chromatography method with mass spectrometric detection (LC-MS/MS) and their pharmacokinetic parameters were calculated by using the Kinetica programme, version 5.0: Cmax, Tmax, PIK (0-72), PIK (0-∞), T1/2, and Ke. Results: The median values of both itraconazole and hydroxyitraconazole were lower in women in comparison to men during the whole period of observation. Moreover, median values of Cmax, PIK(0-72) and PIK(0-∞) parameters were also significantly lower in women, concerning both itraconazole (p=0.005, 0.036 and 0.036, respectively) and its metabolite (p=0.004, 0.010 and 0.044, respectively). Elimination parameters - T1/2 and Ke did not differ between genders. Conclusion: Women were less exposed to itraconazole and its active metabolite than men following an oral application of the drug, possibly as a result of lower bioavailability due to a more intense pre-systemic metabolism, as a result of a higher expression and/or activity of the isoform enzyme, which metabolises itraconazole, and which would need to be confirmed by pharmacogenomic analysis.

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Pharmacokinetic and Tolerability Comparison of Sustained and Immediate Release Oral Formulations of Nifedipine Tablet Formulations: A Single-Dose, Randomized, Open-Label, Two-Period, Two-Way Crossover Study in Healthy, Fasting Egyptian Male Volunteers

Drug Research ◽

10.1055/a-1035-9212 ◽

2019 ◽

Vol 70 (02/03) ◽

pp. 91-96

Author(s):

Soha Mahmoud El-Masry ◽

Noha Mahmoud El-Khodary

Keyword(s):

Single Dose ◽

Plasma Concentrations ◽

Immediate Release ◽

Reversed Phase ◽

Channel Blockers ◽

Open Label ◽

Release Formulation ◽

Chromatography Method ◽

Significant Difference ◽

Liquid Chromatography Method

AbstractNifedipine is one of calcium channel blockers that commonly used clinically to treat hypertension and angina in Egyptian patients. A sustained-release (SR) formulation of nifedipine is available in the Egyptian community and administered twice daily. This study aimed to to compare the pharmacokinetics and safety profiles of a 20 mg SR and IR (immediate release) formulation of nifedipine after single-dose administration in healthy Egyptian subjects. Randomized, crossed open-label two- way clinical trial, in 16 healthy adult volunteers, of 24.75±5.20 years, with BMI 23.26±1.756 were assessed. Blood samples were collected at predefined times for 48 h and analyzed for Nifedipine plasma concentrations using validated reversed phase liquid chromatography method with ultraviolet detection. Pharmacokinetics was determined using non- compartmental model pharmacokinetics and analyzed using one-way ANOVA (P≤0.05). Following a single oral administration, SR formulation had a lower Cmax, compared to IR formulation (54.46±17.75 , 107.45±29.85 ng/mL, respectively), and Tmax was significantly longer (2.97 vs. 1.13 h) for the SR and IR formulation, respectively. There was no significant difference between the SR and the IR formulations for AUC0–last and AUC0-∞ (326.7±98.28 vs. 309.27±105.53 ng·h·mL−1 and 380.9 ± 105.24 vs. 334.36±108.1 ng·h·mL−1, respectively). SR formulation of nifedipine showed similar pharmacokinetics to the IR Formulation (F%=1.049), but it additionally allows a less frequent administration. Therefore, The nifedipine SR and IR formulations were well tolerated and displayed comparable safety profiles.

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Pharmacokinetics of Gentamicin C1, C1a, and C2 in Beagles after a Single Intravenous Dose

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.6.1443-1447.2000 ◽

2000 ◽

Vol 44 (6) ◽

pp. 1443-1447 ◽

Cited By ~ 13

Author(s):

Nina Isoherranen ◽

Eran Lavy ◽

Stefan Soback

Keyword(s):

High Performance ◽

Plasma Concentrations ◽

Volume Of Distribution ◽

Pharmacokinetic Analysis ◽

Time Data ◽

Chromatography Method ◽

The Mean ◽

The Difference ◽

Liquid Chromatography Method ◽

Toxicological Significance

ABSTRACT The pharmacokinetics of gentamicin C1, C2, and C1a were studied in six beagles after administration of gentamicin at 4 mg/kg of body weight as a single intravenous bolus dose. Plasma concentrations of the gentamicin components were analyzed with a novel high-performance liquid chromatography method capable of identifying and quantifying each of the components. The pharmacokinetic analysis of the plasma concentration-versus-time data was performed using the noncompartmental approach. The results indicated significant differences in the pharmacokinetic characteristics between the gentamicin components C1, C1a, and C2. The mean residence times of gentamicin C1, C1a, and C2 were 81 ± 13, 84 ± 12, and 79 ± 13 min (mean ± standard deviation), respectively. The half-lives of the respective components were 64 ± 12, 66 ± 12 and 63 ± 12 min. Clearance (CL) of gentamicin C1, 4.62 ± 0.71 ml min−1 kg−1, was significantly higher (P = 0.0156) than CL of gentamicin C1a, 1.81 ± 0.26 ml min−1kg−1, and C2, 1.82 ± 0.25 ml min−1 kg−1. Similarly, the volume of distribution at steady state (V ss) of gentamicin C1, 0.36 ± 0.04 liter kg−1, was significantly higher (P = 0.0156) than the V ss of gentamicin C1a, 0.14 ± 0.01 liter kg−1, and C2, 0.15 ± 0.02 liter kg−1. Tissue binding was considered the most likely cause for the difference. The difference may have clinical and toxicological significance.

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Penetration of ceftibuten into middle ear fluid.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.6.1394 ◽

1996 ◽

Vol 40 (6) ◽

pp. 1394-1396 ◽

Cited By ~ 4

Author(s):

C Lin ◽

P Kumari ◽

R J Perrotta ◽

B E Reidenberg

Keyword(s):

Middle Ear ◽

Pediatric Patients ◽

Acute Otitis Media ◽

Area Under The Curve ◽

Pharmacokinetic Parameters ◽

Chromatography Method ◽

Middle Ear Fluid ◽

Liquid Chromatography Method ◽

Oral Doses ◽

Major Pathogens

The penetration of ceftibuten, an extended-spectrum oral cephalosporin, into middle ear fluid (MEF) was evaluated in pediatric patients during a course of daily oral doses of 9 mg/kg of body weight for 10 days. Plasma and MEF collected at 2, 4, 6, or 12 h after at least 3 days of dosing were analyzed for ceftibuten by a high-pressure liquid chromatography method, and the data were used to calculate pharmacokinetic parameters. Plasma and MEF had almost identical maximum concentrations (Cmax) of ceftibuten (14 micrograms/ml). These Cmax values in MEF during acute otitis media were well in excess of the MIC for 90% of the isolates of each of four major pathogens in this disease. The time to Cmax was longer in MEF (4 h) than in plasma (2 h). Excellent penetration (71%) of ceftibuten into MEF was observed on the basis of the area under the curve ratio (MEF/plasma). These data clearly indicate that ceftibuten penetrated well into the MEF to yield clinically effective concentrations.

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Compartmental Pharmacokinetics of the Antifungal Echinocandin Caspofungin (MK-0991) in Rabbits

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.2.596-600.2001 ◽

2001 ◽

Vol 45 (2) ◽

pp. 596-600 ◽

Cited By ~ 45

Author(s):

Andreas H. Groll ◽

Bryan M. Gullick ◽

Ruta Petraitiene ◽

Vidmantas Petraitis ◽

Myrna Candelario ◽

...

Keyword(s):

High Performance ◽

Pharmacokinetic Model ◽

Area Under The Curve ◽

Apparent Volume ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Chromatography Method ◽

Opportunistic Fungi ◽

The Mean ◽

Liquid Chromatography Method

ABSTRACT The pharmacokinetics of the antifungal echinocandin-lipopeptide caspofungin (MK-0991) in plasma were studied in groups of three healthy rabbits after single and multiple daily intravenous administration of doses of 1, 3, and 6 mg/kg of body weight. Concentrations were measured by a validated high-performance liquid chromatography method and fitted into a three-compartment open pharmacokinetic model. Across the investigated dosage range, caspofungin displayed dose-independent pharmacokinetics. Following administration over 7 days, the mean peak concentration in plasma (C max) ± standard error of the mean increased from 16.01 ± 0.61 μg/ml at the 1-mg/kg dose to 105.52 ± 8.92 μg/ml at the 6-mg/kg dose; the mean area under the curve from 0 h to infinity rose from 13.15 ± 2.37 to 158.43 ± 15.58 μg · h/ml, respectively. The mean apparent volume of distribution at steady state (Vdss) was 0.299 ± 0.011 liter/kg at the 1-mg/kg dose and 0.351 ± 0.016 liter/kg at the 6-mg/kg dose (not significant [NS]). Clearance (CL) ranged from 0.086 ± 0.017 liter/kg/h at the 1-mg/kg dose to 0.043 ± 0.004 liter/kg/h at the 6-mg/kg dose (NS), and the mean terminal half-life was between 30 and 34 h (NS). Except for a trend towards an increasedVdss, there were no significant differences in pharmacokinetic parameters in comparison to those after single-dose administration. Caspofungin was well tolerated, displayed linear pharmacokinetics that fit into a three-compartment pharmacokinetic model, and achieved sustained concentrations in plasma that were multiple times in excess of reported MICs for susceptible opportunistic fungi.

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Single Dose Pharmacokinetic Study of Lithium in Taiwanese/Chinese Bipolar Patients

Australian & New Zealand Journal of Psychiatry ◽

10.3109/00048679809062720 ◽

1998 ◽

Vol 32 (1) ◽

pp. 133-136 ◽

Cited By ~ 11

Author(s):

Ching-Fa Lee ◽

Yong-Yi Yang ◽

Oliver Yoa-Pu Hu

Keyword(s):

Single Dose ◽

Racial Differences ◽

Half Life ◽

Lithium Carbonate ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Overnight Fasting ◽

Ethnic Comparisons ◽

Bipolar Patients ◽

Kinetics Of

Objective: The purpose of this study is to investigate the single dose pharmaco-kinetics of lithium in Taiwanese/Chinese bipolar patients for future interracial comparisons. Method: Eight bipolar patients took 900 mg of lithium carbonate after overnight fasting. Blood samples of 5 mL were taken after 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 7 h, 9 h, 15 h, 25 h and 31 h after dosing. The computer programs CSTRIP and PCNONLIN were used for pharmacokinetic analysis. Results: The pharmacokinetic parameters obtained were as follows: Cmax, 0.970 ± 0.170 (SD) mmoi/L; Tmax, 1.59 ± 0.78 h; AUC31h = 548.9 ± 135.4 mmol.m/L; AUC = 722.6 ± 262.7 mmol.m/L; β-half-life = 16.3 ± 7.18 h; K-half-life = 0.613 ± 0.442 h; CIoral = 1.13 ± 0.39 mL/min/kg; Vd/F = 1.43 ± 0.387 L/kg. Most of the pharmacokinetic parameters were within the ranges reported in investigations of Caucasian subjects. Conclusions: This study showed that racial differences in lithium pharmacokinetics might not exist. We suggest that methodological designs, including method of blood sampling, measurement of lithium, and pharmacokinetic and statistical calculations, be standardised if future cross-ethnic comparisons are to be conducted.

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Estimation of Pharmacokinetic Parameters of Continuous Intravenous Flucloxacillin infusion in the Outpatient Settings (PKFLUCLOX)

10.1101/499848 ◽

2018 ◽

Author(s):

Nilar Lwin ◽

Zheng Liu ◽

Mark Loewenthal ◽

Pauline Dobson ◽

Ji Woong Yoo ◽

...

Keyword(s):

Steady State ◽

Continuous Infusion ◽

Time Course ◽

Plasma Concentrations ◽

Compartment Model ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Device Removal ◽

Standard Dosage

Flucloxacillin, a beta-lactam antibiotic of the penicillin class, is considered first line therapy for methicillin sensitive Staphylococcus aureus (MSSA) in Australia. At our tertiary referral hospital in the home (HITH) program, it has been prescribed in a standard dosage of 8 grams per day by continuous infusion for more than 20 years. The aim of this observational study was to characterize the pharmacokinetic profile of flucloxacillin in patients who receive continuous infusion in the HITH setting, and to undertake population pharmacokinetic analysis performed with NONMEM software by comparing various structural models. This study utilised flucloxacillin concentrations from 44 separate specimens obtained from 23 patients. Twenty-five of these were collected immediately after elastomeric device removal, representing steady-state concentrations, and the remaining 19 were each collected at least 45 minutes after device removal to determine clearance of the drug. Plasma concentrations ranged from 13 to 194 mg/L with median steady-state concentration of 51.5 mg/L and inter-quartile range of 24.6 mg/L. The time-course of flucloxacillin was best described by a 1-compartment model. The best three covariates, CrCL (ΔOFV= -11.7), eGFR (ΔOFV= -5.9) and serum albumin (ΔOFV= -5.8) were found to be equivalent in terms of decreasing the OFV. CrCL was superior in explaining inter individual variability. The best model for flucloxacillin clearance was a one compartment model with CrCL as the sole covariate. The estimated population parameters were 9.5 L for volume of distribution and 8.1 L/h for flucloxacillin clearance.

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Development and Validation of Novel RP-HPLC Method for the Simultaneous Determination of Remogliflozin and Vildagliptin in Bulk and in synthetic Mixture

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i40b32296 ◽

2021 ◽

pp. 338-349

Author(s):

Drashti A. Mandale ◽

Chainesh Shah ◽

Rakesh Jatt

Keyword(s):

Single Dose ◽

Dose Regimen ◽

High Performance ◽

Sglt2 Inhibitor ◽

Hplc Method ◽

Synthetic Mixture ◽

Chromatography Method ◽

Drug Sample ◽

Liquid Chromatography Method

Vildagliptin which is DPP-4 inhibitor and Remogliflozin which is SGLT2 inhibitor in single dose regimen lower blood glucose by separate, complementary mechanisms. Both are glucose dependent, accounting for the low risk of hypoglycaemia during treatment. There is no risk factors associated with this combination and moreover it is single dose regimen. The aim of the present study was to develop and validate a simple, rapid and reproducible gradient high performance reverse phase liquid chromatography method for the estimation of Remogliflozin and Vildagliptin in bulk drug sample and in synthetic mixture using Xterra® Waters C18 column (150 mm×4.6 mm, 5 µm) at 25°C with UV detection at 210 nm and for this gradient mode was used. The compounds were eluted gradiently at a flow rate of 1.0ml/min. The average retention times for Remogliflozin and Vildagliptin were 4.881 and 6.334 min, respectively. The calibration curves were linear (r2 =0.988) over the concentration range 10-200 µg/ml for Remogliflozin and 10-200 µg/ml for Vildagliptin. No spectral or chromatographic interferences from formulation excipients were found and hence it was successfully applied for the determination of Remogliflozin and Vildagliptin in bulk and in synthetic mixture. The accuracy of the proposed method was determined by recovery studies and found to be 98-101%. The proposed method was validated and results conformed to ICH parameters.

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Bioequivalence of levamlodipine besylate tablets in healthy Chinese subjects: A single-dose and two-period crossover randomized study

10.21203/rs.3.rs-47842/v2 ◽

2020 ◽

Author(s):

Li Xin ◽

Chenjing Wang ◽

Ting Li ◽

Yanping Liu ◽

Shuqin Liu ◽

...

Keyword(s):

Single Dose ◽

Randomized Study ◽

Plasma Concentrations ◽

Bioequivalence Study ◽

Pharmacokinetic Parameters ◽

Open Label ◽

Liquid Chromatography Tandem Mass ◽

The Mean ◽

Healthy Chinese ◽

Chinese Subjects

Abstract Background: Levamlodipine, a calcium channel blocker, has been show act as a cardiovascular drug. To compare the pharmacokinetic parameters between levamlodipine (test formulation) at a single dose of 5 mg and amlodipine (reference formulation) at a single dose of 10 mg, the bioequivalence study was carried out.Methods: A single-dose randomized, open-label, two-period crossover study was designed in healthy Chinese subjects. 48 subjects were divided into fasted and fed groups equally. The subjects randomly received the test or reference formulations at the rate of 1:1. Following a 21-day washout period, the alternative formulations were received. The blood samples were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 24, 36, 48, 72, 96, 120, 144, 168 hours later. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine the plasma concentrations of levamlodipine. Adverse events were recorded.Results: The 90% confidence intervals (CIs) of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ under both fasted and fed conditions were within the prespecified bioequivalence limits between 80~125%. Under fasted conditions, 24 subjects were enrolled and completed the study. The mean Cmax was (2.70±0.49) ng/mL, AUC0-t was (141.32±36.24) ng×h/mL and AUC0-∞ was (157.14±45.65) ng×h/mL after a single dose of 5 mg levamlodipine. The mean Cmax was (2.83±0.52) ng/mL, AUC0-t was (153.62±33.96) ng×h/mL and AUC0-∞ was (173.05±41.78) ng×h/mL after a single dose of 10 mg amlodipine. Under fed conditions, 24 subjects were enrolled and completed the study. The mean Cmax was (2.73±0.55) ng/mL, AUC0-t was (166.93±49.96) ng×h/mL and AUC0-∞ was (190.99±70.89) ng×h/mL after a single dose of 5 mg levamlodipine. The mean Cmax was (2.87±0.81) ng/mL AUC0-t was (165.46±43.58) ng×h/mL and AUC0-∞ was (189.51±64.70) ng×h/mL after a single dose of 10 mg amlodipine. Serious adverse event was not observed.Conclusion: The trial confirmed that levamlodipine at a single dose of 5 mg and amlodipine at a single dose of 10 mg were bioequivalent under both fasted condition and fed condition.Trial registration: Cinicaltrials, NCT04411875. Registered 3 June 2020 - Retrospectively registered, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0009W1Q&selectaction=Edit&uid=U00050YQ&ts=3&cx=-6iqkm8

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Plasma Concentrations of Boswellic Acids in Fasting Healthy Humans Supplemented with a Water-Soluble Boswellia Extract (78% AKBA) vs. Reference Boswellia Extract (30% AKBA) (P06-005-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.p06-005-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Barbara Davis ◽

Krishanu Sengupta ◽

Venkata Krishnaraju Alluri ◽

Trimurtulu Golakoti

Keyword(s):

Plasma Concentrations ◽

Water Soluble ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Open Label ◽

Oral Ingestion ◽

Post Dose ◽

Geometric Means ◽

Funding Sources ◽

Healthy Humans

Abstract Objectives A randomized, open label, balanced, two-way crossover study compared the oral bioavailability and pharmacokinetic profiles of two Boswellia products standardized to 3-O-acetyl-11-Keto-β-boswellic acid (AKBA). Methods Twenty-two fasted male participants completed the study. They received a single oral-dose of water-soluble Boswellia extract 78% (LI51202F1) or the standard Boswellia extract 30% (5-Loxin) at 30 mg AKBA equivalent with 240 mL water on 2 separate occasions 12 days apart. Plasma AKBA and KBA were analyzed using a LC-MS/MS in pre- (0 hr) and post-dose (00.50, 01.00, 01.50, 02.00, 02.50, 03.00, 04.00, 08.00, 12.00 and 24.00 hrs) blood samples. Pharmacokinetic analysis was performed using WinNonlin® version 7.0 (Pharsight corporation, USA). Results Comparative analysis of the pharmacokinetic parameters showed LI51202F1 had higher (111.11%) Cmax for AKBA vs. 5-Loxin. The bioavailability indicated by Geometric means of AUC0-t and AUC0-∞ were 25.49% and 16.13% higher in LI51202F1 than 5-Loxin. Conclusions The present study demonstrates that oral ingestion of water soluble and standard Boswellia extracts resulted in similar bioavailability. Interestingly, the water-soluble version exhibited higher Cmax and AUC values, which could be attributed to the improved solubility of LI51202F1. Funding Sources Laila Nutraceuticals.

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Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients

Current Drug Metabolism ◽

10.2174/1389200220666190701094756 ◽

2019 ◽

Vol 20 (7) ◽

pp. 592-600 ◽

Cited By ~ 2

Author(s):

Zhiqi Wang ◽

Nan Zhang ◽

Chaoyang Chen ◽

Shuqing Chen ◽

Junyu Xu ◽

...

Keyword(s):

Pharmacokinetic Model ◽

Genetic Factors ◽

Plasma Concentrations ◽

Chinese Patients ◽

Estimation Methods ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Mixed Effect ◽

The Impact

Background: The Pharmacokinetics of Methotrexate (MTX) has been reported to show significant intersubject variability. MTX is metabolized by SHMT1 and transported by OATP1B1 and OATP1B3 both of which show genetic polymorphisms. The non-genetic and genetic factors may influence the pharmacokinetics of MTX. Objective: This study aimed to determine the pharmacokinetic parameters of MTX in Chinese patients and to investigate the effect of various non-genetic factors and genetic variants of OATP1B1, OATP1B3 on MTX’s pharmacokinetics. Method: MTX concentration and clinical characteristics data were collected from 71 rheumatoid arthritis patients. For each patient, SLC19A1, SHMT1, OATP1B1, and OATP1B3 genotyping were tested. Population pharmacokinetic analysis was performed by Nonlinear Mixed-Effect Modeling (NONMEM). MTX pharmacokinetic properties analysis was executed using the one-compartment pharmacokinetic model which incorporated first-order conditional estimation methods with interaction. Besides, the impact of genetic factors and demographic factors on MTX disposition were explored. Results: All the genotypes of steady-state plasma concentrations and OATP1B1 rs4149056, OATP1B1 rs2306283, and OATP1B3 rs7311358 were determined. The detected blood drug concentration reached the standard. Genotypes were all measured. At the same time, the population pharmacokinetic model of methotrexate was obtained CL(L·h-1) =8.25× e0.167× SNP (SNP: SLCO1B1 388A/A=3; SLCO1B1 388A/G=2; SLCO1B1 388G/G=1); V(L)= 32.8; Ka(h- 1)=1.69. Conclusion: : In our study, it was showed that OATP1B1-388 G>A SNP had a significant effect on CL/F. The factor should be considered when determining MTX dosing. However, prospective studies with a large number of participants are needed to validate the results of this study.

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