Pharmacokinetics of C1 Esterase Inhibitor, Human (Pasteurized) in Subjects with Hereditary Angioedema.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1031-1031
Author(s):  
Wolfhart Kreuz ◽  
Inmarculada Martinez-Saguer ◽  
Hildegard Stoll ◽  
Sigurd Knaub ◽  
Thomas Klingebiel
Keyword(s):  
Plasma Concentration ◽  
Hereditary Angioedema ◽  
Half Life ◽  
Compartment Model ◽  
Rapid Onset ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
On Demand ◽  
The Mean

Abstract Hereditary and acquired deficiencies in C1 inhibitor (C1-INH) function can result in potentially life-threatening attacks of hereditary angioedema (HAE). A highly purified and pasteurized C1-INH concentrate has been used effectively as prophylaxis against and treatment for angioedema attacks in patients with hereditary C1-INH deficiencies, but relatively little is known about its pharmacokinetic properties. Objective: To evaluate the pharmacokinetics and in vivo recovery (IVR) of C1-INH concentrate (Berinert®P) in two groups of patients with hereditary angioedema (HAE) receiving this preparation either as individual replacement therapy (IRT, regular, immediate treatment of first HAE symptoms in patients with frequent and severe attacks) or as on-demand treatment. Methods: Forty subjects (15 under IRT, 25 under on-demand treatment) with HAE received intravenous injections of C1-INH (542–1,617 U) in an attack-free interval in a prospective, open, uncontrolled, single-center study. Blood was sampled for determination of C1-INH with a commercially available functional chromogenic assay for up to 72 hours after dosing. Pharmacokinetic parameters were calculated using a single-compartment model and IVR was determined using standard methods. Results: The mean (± SD) time to maximum plasma concentration (Tmax) for C1-INH administered in patients under IRT was 1.3 ± 2.1 hours, the area under the time versus plasma concentration curve (AUC) was 20.5 ± 19.1 hour•U/mL, the elimination half-life (t½) was 33.3 ± 19.8 hours, mean residence time (MRT) was 48.0 ± 28.5 hours, total body clearance (Cl) was 1.1 ± 0.6 mL/kg/hour, and volume of distribution at steady state (Vss) was 39.5 ± 9.9 mL/kg. The respective values for patients treated on demand were 2.9 ± 6.5 hours, 20.0 ± 14.5 hour•U/mL, 43.9 ± 22.4 hours, 63.4 ± 32.3 hours, 1.2 ± 1.0 mL/kg•hour, and 51.4 ± 10.9 mL/kg. The mean IVRs for IRT and on-demand treatment were 108.2 ± 48.3% and 85.8 ± 28.3%, respectively. Children tended to have slightly lower half-life and a slightly higher Vss compared to adults. Conclusions: C1-INH concentrate has a short Tmax and a long, t½ and MRT consistent with the rapid onset of clinical efficacy for this preparation in subjects suffering angioedema attacks and the ability to effectively carry out IRT with injections administered every 2–5 days. This analysis provides to our knowledge the most comprehensive pharmacokinetic evaluation in subjects with HAE.

MSDD1, a Prodrug of 5-Hydroxymethyl-2-Furfural (5HMF), Prolongs the Antisickling Effect of 5HMF in Transgenic Sickle Mice.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3576-3576
Author(s):  
Osheiza Abdulmalik ◽  
Martin K. Safo ◽  
Richmond Danso-Danquah ◽  
Jisheng Yang ◽  
Qiukan Chen ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Half Life ◽  
Slow Release ◽  
Treated Group ◽  
Pharmacokinetic Data ◽  
Maximum Plasma ◽  
Concentration Time ◽  
Terminal Half Life ◽  
Hb S

Abstract We recently reported that 5-hydroxymethyl-2-furfural (5HMF), a 5-membered heterocyclic aldehyde, had a potent anti-sickling effect in both in vitro tests and in vivo studies using transgenic (Tg) sickle mice. 5HMF is quickly absorbed and covalently binds with sickle hemoglobin (Hb S) to form a high-affinity reversible Schiff-base adduct. Although 5HMF is readily bioavailable after oral administration to Tg sickle mice, preliminary pharmacokinetic data suggest that its terminal half-life (T1/2 = 1.5 ± 0.6 hr) may be too short to exert a sustained anti-sickling effect in vivo for a sufficient length of time. We also determined that although 100mg/kg inhibited sickling and prevented the development of pulmonary sequestration in Tg sickle mice exposed to severe hypoxic conditions, high levels of modified Hb in the blood were sustained for only about 4hrs. Since a significant anti-sickling effect is observed by modifying 50% of Hb S molecules, a reduction in dosage combined with less frequent intake seems to be a more attractive and acceptable option. Based on this, we designed a slow-release prodrug of 5HMF by protecting the aldehyde group with L-cysteine to form the thiazolidine complex (MSDD1), expecting that the prodrug would slowly release active 5HMF into the bloodstream over a longer period of time, resulting in a longer half-life for 5HMF. To compare the pharmacokinetic profiles of these two compounds, 2 groups of Tg sickle mice (6 mice per group) were treated orally with a single 100 mg/kg dose of either 5HMF or its slow-release form, MSDD1. Blood samples (~20 μl each) were collected via retro-orbital venipuncture under anesthesia into EDTA tubes at 20 min, 40 min, 1 hr and every hour afterwards for 7 hours. Plasma from each sample was deproteinized, 10 μl of each sample was diluted 20-fold and analyzed by reversed-phase HPLC for quantification of 5HMF present in the blood. A non-compartmental pharmacokinetic model with first-order elimination rate was used to determine the plasma concentration-time data. The area under the plasma concentration curve (AUC), terminal half-life (T1/2 ), peak concentration time (Tmax), maximum plasma concentration (Cmax), and the mean resident time (MRT) were determined using PK Solutions 2.0 software (SUMMIT Research Services, Montrose, CO, USA). The AUC of the group that received MSDD1 did not significantly differ from the AUC of those that received 5HMF (430 ± 32 μg/ml/min vs. 410 ± 24 μg/ml/min). However, in the group that received MSDD1, both the T1/2 and Tmax increased 2-fold (2.9 ± 0.32 hr vs. 1.5 ± 0.6 hr, and 1hr vs. 0.5 hr, respectively). The MRT also increased from 2.3 ± 0.0.16 hr in the 5HMF-treated group to 5.8 ± 0.26 hr in the MSDD1-treated group, although the Cmax was reduced almost 3-fold in the MSDD1-treated mice at 70 ± 12 μg/ml, compared to 180.7 ± 32.6 μg/ml in 5HMF-treated mice We conclude that MSDD1, a slow-release prodrug of 5HMF seems to provide the possibility of administering a single oral daily dose, and may be a suitable treatment option for sickle cell disease patients in the future.

Pharmacokinetics of dibromodulcitol in humans: a phase I study.

1986 ◽  
Vol 4 (5) ◽  
pp. 753-761 ◽  
Author(s):  
S L Kelley ◽  
W P Peters ◽  
J Andersen ◽  
E A Furlong ◽  
E Frei ◽  
...  
Keyword(s):  
Phase I ◽  
Half Life ◽  
Phase I Study ◽  
Drug Level ◽  
Compartment Model ◽  
Hepatic Function ◽  
Apparent Volume ◽  
Pharmacokinetic Parameters ◽  
Elimination Constant ◽  
The Mean

A combined clinical and pharmacokinetic phase I study of the substituted hexitol dibromodulcitol (DBD), administered as a single oral monthly dose, has been performed. Twenty-three patients with advanced neoplasms received DBD doses ranging from 600 to 1,800 mg/m2 body surface area (BSA). The dose-limiting toxicity was myelosuppression, with both significant granulocytopenia and thrombocytopenia occurring at dose levels of 1,500 to 1,800 mg/m2. The average pharmacokinetic parameters for DBD, calculated on the basis of a one-compartment model with first-order absorption and elimination, include the elimination constant, .005 +/- .002/min; absorption constant, .012 +/- .009/min; and an apparent volume of distribution, 1.03 +/- .4 L/kg. The area under the drug concentration curve (AUC) and the peak drug level (Cmax) were linearly related to the dose administered (P less than .001). The mean AUC was 18.7 +/- 6.1 mmol/L min, and the mean Cmax was 47.1 +/- 16.8 mumol/L when normalized to a DBD dose of 1 gm/m2. The elimination constant was significantly reduced in patients with abnormal hepatic function (P less than .01). The elimination constant was not correlated with renal function. The half-life of DBD in plasma (158 minutes) was considerably shorter than the four-to eight-hour half-life of total radioactivity in plasma measured by previous investigators following the administration of radiolabeled DBD.

scholarly journals Effect of Food on the Pharmacokinetics of Gliclazide 60 mg Modified Release Tablet in Healthy Caucasian Volunteers

2018 ◽  
Vol 64 (4) ◽  
pp. 161-168
Author(s):  
Diana Pop ◽  
Ana-Maria Gheldiu ◽  
Monica Oroian ◽  
Adriana Marcovici ◽  
Sandeep Bhardwaj ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Food Effect ◽  
Statistical Significance ◽  
Pharmacokinetic Profile ◽  
Maximum Plasma Concentration ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Modified Release ◽  
Pharmaceutical Industries ◽  
The Mean

AbstractObjective: To evaluate the food effect on glicazide disposition in clinical trials conducted on healthy Caucasian volunteers who were given a new modified release oral formulation of Gliclazide 60 mg developed by Sun Pharmaceutical Industries, India.Methods: The studies were designed as open-label, randomized, single-dose, crossover studies that consisted of two periods. During each study, venous blood samples were taken before and after drug administration up to 96 hours. Subsequently, individual plasma profiles were determined and non-compartmental method was employed for the assessment of food effect on the pharmacokinetic profile of gliclazide. The statistical significance of differences for the main pharmacokinetic parameters was evaluated by ANOVA test, for p < 0.05 statistical significance was decided. The relative profiles of absorption of gliclazide were obtained by mathematical deconvolution. All calculation were performed by Phoenix WinNonlin®.Results: High-fat, high-calorie meal decreased gliclazide exposure. The mean maximum plasma concentration decreased with 14%, while the mean total area under the plasma concentration-time profile registered a 17% decrease. The elimination half-lives under fasted and fed conditions were comparable and the time to maximum plasma concentration was shortened under fed condition. Safety evaluation showed that overall gliclazide was well tolerated under both fasted and fed condition.Conclusions: The statistical analysis revealed the lack of food effect on the new modified release tablets of Gliclazide 60 mg. However, before stating a definite conclusion regarding the food effect on gliclazide pharmacokinetic profile, additional studies on patients with type 2 diabetes mellitus should be conducted.

scholarly journals Serum bactericidal activities and comparative pharmacokinetics of meropenem and imipenem-cilastatin.

1996 ◽  
Vol 40 (1) ◽  
pp. 105-109 ◽  
Author(s):  
M Dreetz ◽  
J Hamacher ◽  
J Eller ◽  
K Borner ◽  
P Koeppe ◽  
...  
Keyword(s):  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Dose Administration ◽  
Microdilution Method ◽  
Two Compartment Model ◽  
Elimination Half ◽  
Renal Clearances ◽  
The Mean ◽  
Bactericidal Activities

The pharmacokinetics and serum bactericidal activities (SBAs) of imipenem and meropenem were investigated in a randomized crossover study. Twelve healthy male volunteers received a constant 30-min infusion of either 1 g of imipenem plus 1 g of cilastatin or 1 g of meropenem. The concentrations of the drugs in serum and urine were determined by bioassay and high-pressure liquid chromatography. Pharmacokinetic parameters were based on an open two-compartment model and a noncompartmental technique. At the end of infusion, the mean concentrations of imipenem and meropenem measured in serum were 61.2 +/- 9.8 and 51.6 +/- 6.5 mg/liter, respectively; urinary recoveries were 48.6% +/- 8.2% and 60.0% +/- 6.5% of the dose in 12 h, respectively; and the areas under the concentration-time curve from time zero to infinity were 96.1 +/- 14.4 and 70.5 +/- 10.3 mg.h/liter, respectively (P < or = 0.02). Imipenem had a mean half-life of 66.7 +/- 10.4 min; that of meropenem was 64.4 +/- 6.9 min. The volumes of distribution at steady state of imipenem and meropenem were 15.3 +/- 3.3 and 18.6 +/- 3.0 liters/70 kg, respectively, and the mean renal clearances per 1.73 m2 were 85.6 +/- 17.6 and 144.6 +/- 26.0 ml/min, respectively. Both antibiotics were well tolerated in this single-dose administration study. The SBAs were measured by the microdilution method of Reller and Stratton (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977) against 40 clinically isolated strains. Mean reciprocal bactericidal titers were measured 1 and 6 h after administration. After 1 and 6 h the median SBAs for imipenem and meropenem, were 409 and 34.9 and 97.9 and 5.8, respectively, against Staphylococcus aureus, 19.9 and 4.4 and 19.4 and 4.8, respectively, against Pseudomonas aeruginosa, 34.3 and 2.2 and 232 and 15.5, respectively, against Enterobacter cloacae, and 13.4 and 2.25 and 90.7 and 7.9, respectively, against Proteus mirabilis. Both drugs had rather short biological elimination half-lives and a predominantly renal route of elimination. Both carbapenems revealed high SBAs against clinically important pathogens at 1 h; meropenem had a higher SBA against E. cloacae and P. mirabilis, and the SBA of imipenem against S. aureus was greater than the SBA of meropenem.

Withdrawal of cefoperazone with milk after intramammary administration in dairy cows – prospective and retrospective analysis

2017 ◽  
Vol 20 (2) ◽  
pp. 261-268
Author(s):  
A. Burmańczuk ◽  
T. Grabowski ◽  
T. Błądek ◽  
C. Kowalski ◽  
P. Dębiak
Keyword(s):  
Dairy Cows ◽  
Half Life ◽  
Drug Distribution ◽  
Compartment Model ◽  
Clinical Mastitis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Lactation Period ◽  
Milk Samples ◽  
Drug Concentrations

Abstract The aim of the study was to carry out retrospective and prospective comparative analyses of the pharmacokinetics of CEF after single intramammary (IMM) administration in cows. The prospective study (study A) was conducted on 9 dairy cows of the Polish Black-White race with clinical mastitis during the lactation period. Milk samples were collected at 2, 4, 6, 8, 10, 24, 36, 48, 72 and 84 h after single IMM administration of 250 mg of CEF to one quarter. Drug concentrations in milk samples were determined by HPLC-MS/MS technique and the results of the pharmacokinetic analysis were compared to those obtained in previous studies based on the microbiological (study B) and HPLC-UV methods (study C and D). Pharmacokinetic parameters were calculated based on adapted two-compartment model of drug distribution. One of the findings of the comparison of the analysed investigations is that the CEF kinetics determined with the microbiological method is consistent with the results obtained by the authors of this paper. Both studies yielded similar results of the key pharmacokinetic parameters related to the level of the drug distribution to tissues and elimination half-life. In the pharmacodynamic analysis, the observations in all four studies were entirely consistent and have shown lower values of T>MIC90 in healthy animals and significantly higher values in infected dairy cows. The comparison of studies A, B, C, and D revealed that the time of complete CEF wash-out of 90.90% varied and amounted to 5.7, 8.0, 2.2, and 2.2 days after administration of the drug, respectively. It was confirmed that not only the type of the analytical method but also correct sampling have a significant impact on determination of the correct value of the drug half-life after IMM administration. The comparative analysis of studies in which the milk yield was high and low allows a conclusion that this parameter in the case of CEF has no significant effect on T>MIC90.

Pharmacokinetics and Tissue Residues of Sulfathiazole and Sulfamethazine in Pigs

1994 ◽  
Vol 57 (9) ◽  
pp. 796-801 ◽  
Author(s):  
LIEVE S. G. VAN POUCKE ◽  
CARLOS H. VAN PETEGHEM
Keyword(s):  
Intravenous Injection ◽  
Half Life ◽  
Intramuscular Injection ◽  
Compartment Model ◽  
Absolute Bioavailability ◽  
Pharmacokinetic Parameters ◽  
Tissue Concentrations ◽  
Single Intravenous Injection ◽  
The Individual ◽  
Residue Study

The plasma pharmacokinetics and tissue penetration of sulfathiazole (ST) and sulfamethazine (SM) after intravenous and intramuscular injection in pigs were studied. Following a single intravenous dose of 40 mg ST/kg of bodyweight or 80 mg SM/kg of bodyweight, the plasma ST and SM concentrations were best fitted to a two-compartment model. The areas under the curve were 447 ± 39 and 1485 ± 41 mg/h/L, clearances were 0.090 ± 0.007 and 0.054 ± 0.001 L/kg/h, volumes of distribution were 1.16 ± 0.16 and 0.77 ± 0.06 L/kg, half-lifes in distribution phase were l.18 ± 0.57 and 0.23 ± 0.16 h and half-lifes in eliminations phase were 9.0 ± l.6 and 9.8 ± 0.6 h. When the two compounds were administered simultaneously as a single intravenous injection, the pharmacokinetic parameters for ST were not significantly different. The values for SM show statistical differences for some important parameters: α, β and the AUC0–&gt;∞ were significantly decreased and t1/2α, Vd and CIB were significantly increased. It can be concluded that after a single intravenous injection of 40 mg/kg, sulfathiazole has a high tl/2β resulting in higher tissue concentrations. This half-life, which is higher than what is reported in the literature, is not influenced by the simultaneous presence of sulfamethazine. The tl/2β for sulfamethazine after a single intravenous injection of 80 mg/kg is comparable to the data from the literature and is not influenced by the presence of sulfathiazole. Sulfathiazole and SM were also administered simultaneously as an intramuscular injection to healthy pigs at a dosage of 40 and 80 mg/kg bodyweight. Pharmacokinetic experiments were conducted on three pigs. From this pharmacokinetic study it can be concluded that upon a single intramuscular administration of 40 mg/kg of ST and 80 mg/kg of SM the absolute bioavailability in pigs is 0.92 ± 0.04 for ST and l.01 ± 0.07 for SM. Six pigs received five intramuscular im) injections as a single dose of ST and SM every 24 h for five consecutive days for the residue study. The pigs were slaughtered at different times after the last dose was given and samples were taken from various tissues and organs. Concentrations were determined by a microbiological method and a HPTLC method. No edible tissue contained more than 100 μg/kg of the individual sulfonamides after 10 days of withdrawal. It means that adult animals which have a shorter half-life and thus lower tissue concentrations will certainly meet the economic community EC) maximum residue limits after a 10 days withdrawal period.

The Comparative Pharmacodynamics of Remifentanil and Its Metabolite, GR90291, in a Rat Electroencephalographic Model 

1999 ◽  
Vol 90 (2) ◽  
pp. 535-544 ◽  
Author(s):  
Eugene H. Cox ◽  
Mariska W. E. Langemeijer ◽  
Josy M. Gubbens-Stibbe ◽  
Keith T. Muir ◽  
Meindert Danhof
Keyword(s):  
Steady State ◽  
Time Course ◽  
Parent Drug ◽  
Volume Of Distribution ◽  
Pharmacodynamic Model ◽  
Pharmacokinetic Parameters ◽  
Maximal Effect ◽  
Total Blood ◽  
The Mean

Background The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model. Methods Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood. Results Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 microg/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920+/-110 ml x min(-1) x kg(-1) and 1.00+/-0.93 l/kg for remifentanil and 15+/-2 ml x min(-1) x kg(-1) and 0.56+/-0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25+/-5% and 0.30+/-0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109+/-12 microV, 9.4+/-0.9 ng/ml, and 2.2+/-0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000+/-9,000 microg/ml and 2.5+/-0.4, respectively (n = 6). Conclusions Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.

scholarly journals Safety, toleration, and pharmacokinetics of intravenous azithromycin.

1996 ◽  
Vol 40 (11) ◽  
pp. 2577-2581 ◽  
Author(s):  
D R Luke ◽  
G Foulds ◽  
S F Cohen ◽  
B Levy
Keyword(s):  
Half Life ◽  
Active Drug ◽  
Slow Release ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Concentration Time ◽  
Elimination Half ◽  
The Mean ◽  
Male Subjects

To date, the clinical pharmacology of large intravenous doses of azithromycin has not been described. In the present study, single 2-h intravenous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and two received placebo) of healthy male subjects. Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [good] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous infusion. Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cramping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithromycin was well tolerated. Because of the standardized 1-mg/ml infusates, all subjects in the 4-g dosing group complained of an urgent need to urinate. There were no consistent trends in endogenous motilin levels throughout the study. The maximum concentration of azithromycin in serum (10 micrograms/ml after a 4-g dose) and the area under the concentration-time curve (82 micrograms.h/ml after a 4-g dose) were dose related. The mean pharmacokinetic parameters were an elimination half-life of 69 h, total systemic clearance of 10 ml/min/kg, and a volume of distribution at steady state of 33.3 liters/kg. The pharmacokinetic results suggest that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug. Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable concentrations may persist in serum for 10 days or more.

scholarly journals Pharmacokinetic Profile of μSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats

2015 ◽  
Vol 10 (9) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Rosario Russo ◽  
Angelo Mancinelli ◽  
Michele Ciccone ◽  
Fabio Terruzzi ◽  
Claudio Pisano ◽  
...  
Keyword(s):  
Oral Administration ◽  
Plasma Concentrations ◽  
Compartmental Analysis ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Sprague Dawley ◽  
Time Curve ◽  
Maximum Plasma Drug Concentration

Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (μSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t1/2), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with μSMIN Plus™ compared with animals treated with micronized diosmin. In particular, μSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for μSMIN Plus™, which may represent a new tool for CVI management.

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.

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