scholarly journals Pharmacokinetics and Distribution over the Blood-Brain Barrier of Zalcitabine (2′,3′-Dideoxycytidine) and BEA005 (2′,3′-Dideoxy-3′-Hydroxymethylcytidine) in Rats, Studied by Microdialysis

1998 ◽  
Vol 42 (9) ◽  
pp. 2174-2177 ◽  
Author(s):  
Natalia Borg ◽  
Lars Ståhle
Keyword(s):  
Protein Binding ◽  
Half Life ◽  
Extracellular Fluid ◽  
Volume Of Distribution ◽  
Time Curve ◽  
Concentration Time ◽  
Water Partition Coefficient ◽  
The Mean ◽  
The Brain

ABSTRACT Microdialysis was applied to sample the unbound drug concentration in the extracellular fluid in brain and muscle of rats given zalcitabine (2′,3′-dideoxycytidine; n = 4) or BEA005 (2′,3′-dideoxy-3′-hydroxymethylcytidine; n = 4) (50 mg/kg of body weight given subcutaneously). Zalcitabine and BEA005 were analyzed by high-pressure liquid chromatography with UV detection. The maximum concentration of zalcitabine in the dialysate (C max) was 31.4 ± 5.1 μM (mean ± standard error of the mean) for the brain and 238.3 ± 48.1 μM for muscle. The time to C max was found to be from 30 to 45 min for the brain and from 15 to 30 min for muscle. Zalcitabine was eliminated from the brain and muscle with half-lives 1.28 ± 0.64 and 0.85 ± 0.13 h, respectively. The ratio of the area under the concentration-time curve (AUC) (from 0 to 180 min) for the brain and the AUC for muscle (AUC ratio) was 0.191 ± 0.037. The concentrations of BEA005 attained in the brain and muscle were lower than those of zalcitabine, withC maxs of 5.7 ± 1.4 μM in the brain and 61.3 ± 12.0 μM in the muscle. The peak concentration in the brain was attained 50 to 70 min after injection, and that in muscle was achieved 30 to 50 min after injection. The half-lives of BEA005 in the brain and muscle were 5.51 ± 1.45 and 0.64 ± 0.06 h, respectively. The AUC ratio (from 0 to 180 min) between brain and muscle was 0.162 ± 0.026. The log octanol/water partition coefficients were found to be −1.19 ± 0.04 and −1.47 ± 0.01 for zalcitabine and BEA005, respectively. The degrees of plasma protein binding of zalcitabine (11% ± 4%) and BEA005 (18% ± 2%) were measured by microdialysis in vitro. The differences between zalcitabine and BEA005 with respect to the AUC ratio (P = 0.481), half-life in muscle (P = 0.279), and level of protein binding (P = 0.174) were not statistically significant. The differences were statistically significant in the case of the half-life in the brain (P = 0.032), clearance (P = 0.046), volume of distribution (P = 0.027) in muscle, and octanol/water partition coefficient (P = 0.019).

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 Pharmacokinetics of Nelfinavir and Efavirenz in Antiretroviral-Naïve, Human Immunodeficiency Virus-Infected Subjects when Administered Alone or in Combination with Nucleoside Analog Reverse Transcriptase Inhibitors

2005 ◽  
Vol 49 (8) ◽  
pp. 3558-3561 ◽  
Author(s):  
Patrick F. Smith ◽  
Gregory K. Robbins ◽  
Robert W. Shafer ◽  
Hulin Wu ◽  
Song Yu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Half Life ◽  
Pharmacokinetic Studies ◽  
Reverse Transcriptase Inhibitors ◽  
Time Curve ◽  
Minimum Concentration ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
The Mean

ABSTRACT Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir, or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics.

scholarly journals Pharmacokinetics of a Fluoronaphthyridone, Trovafloxacin (CP 99,219), in Infants and Children following Administration of a Single Intravenous Dose of Alatrofloxacin

2000 ◽  
Vol 44 (5) ◽  
pp. 1195-1199 ◽  
Author(s):  
John S. Bradley ◽  
Gregory L. Kearns ◽  
Michael D. Reed ◽  
Edmund V. Capparelli ◽  
John Vincent
Keyword(s):  
Volume Of Distribution ◽  
Intravenous Dose ◽  
Pharmacokinetic Parameters ◽  
Single Intravenous Dose ◽  
Average Standard Deviation ◽  
Time Curve ◽  
Concentration Time ◽  
Age Related ◽  
The Mean ◽  
In Infants And Children

ABSTRACT The pharmacokinetics of trovafloxacin following administration of a single intravenous dose of alatrofloxacin, equivalent to 4 mg of trovafloxacin per kg of body weight, were determined in 6 infants (ages 3 to 12 months) and 14 children (ages, 2 to 12 years). There was rapid conversion of alatrofloxacin to trovafloxacin, with an average ± standard deviation (SD) peak trovafloxacin concentration determined at the end of the infusion of 4.3 ± 1.4 μg/ml. The primary pharmacokinetic parameters (average ± SD) analyzed were volume of distribution at steady state (1.6 ± 0.6 liters/kg), clearance (151 ± 82 ml/h/kg), and half-life (9.8 ± 2.9 h). The drug was well tolerated by all children. There were no age-related differences in any of the pharmacokinetic parameters studied. Less than 5% of the administered dose was excreted in the urine over 24 h. On the basis of the mean area under the concentration-time curve of 30.5 ± 10.1 μg · h/ml and the susceptibility (≤0.5 μg/ml) of common pediatric bacterial pathogens to trovafloxacin, dosing of 4 mg/kg/day once or twice daily should be appropriate.

scholarly journals Lack of Effect of Experimental Hypovolemia on Imipenem Muscle Distribution in Rats Assessed by Microdialysis

2005 ◽  
Vol 49 (12) ◽  
pp. 4974-4979 ◽  
Author(s):  
Sandrine Marchand ◽  
Claire Dahyot ◽  
Isabelle Lamarche ◽  
Elodie Plan ◽  
Olivier Mimoz ◽  
...  
Keyword(s):  
Jugular Vein ◽  
Extracellular Fluid ◽  
Volume Of Distribution ◽  
Distribution Characteristics ◽  
Time Curve ◽  
Concentration Time ◽  
Leg Muscle ◽  
And Control ◽  
Initial Blood ◽  
Awake Rats

ABSTRACT The aim of this study was to investigate the influence of hypovolemia on the distribution of imipenem in muscle extracellular fluid determined by microdialysis in awake rats. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Imipenem recoveries in muscle and blood were determined in each rat by retrodialysis by drug before drug administration. Hypovolemia was induced by removing 40% of the initial blood volume over 30 min. Imipenem was infused intravenously at a dose of 70 mg · kg−1 over 30 min, and microdialysis samples were collected for 120 min from hypovolemic (n = 8) and control (n = 8) rats. The decay of the free concentrations in blood and muscle with time were monoexponential, and the concentration profiles in muscle and blood were virtually superimposed in both groups. Accordingly, the ratios of the area under the concentration-time curve (AUC) for tissue (muscle) to the AUC for blood were always virtually equal to 1. Hypovolemia induced a 23% decrease in the clearance (P < 0.05) of imipenem, with no statistically significant alteration of its volume of distribution. This study showed that imipenem elimination was altered in hypovolemic rats, probably due to decreased renal blood flow, but its distribution characteristics were not. In particular, free imipenem concentrations in blood and muscle were always virtually identical.

Metronidazole Elimination is Preserved in the Elderly

1990 ◽  
Vol 9 (3) ◽  
pp. 155-159 ◽  
Author(s):  
Steffen Loft ◽  
Charlotte Egsmose ◽  
Jesper Sonne ◽  
Henrik Enghusen Poulsen ◽  
Martin Døssing ◽  
...  
Keyword(s):  
Old Age ◽  
Half Life ◽  
Renal Excretion ◽  
The Elderly ◽  
Volume Of Distribution ◽  
Time Curve ◽  
Concentration Time ◽  
Age Related ◽  
Young Subjects ◽  
Hydroxy Metabolite

1 The disposition of metronidazole and its major metabolites was compared in 11 subjects aged 86 ± 6 years and 8 aged 30 ± 6 years. 2 The plasma clearance of metronidazole was 1.20 ± 0.53 and 1.25 ± 0.22 ml min-1 kg -1, the volume of distribution 0.77 ± 0.27 and 0.77 ± 0.09 1 kg -1 and the half-life 7.8 ± 1.9 and 7.2 ± 0.9 h in elderly and young subjects, respectively (P > 0.05). 3 The area under the plasma concentration-time curve of the hydroxy metabolite was 32 ± 14 and 21 ± 3 mM min-1 (P < 0.05) whereas its half-life was 21 ± 14 and 12 ± 2 h (P < 0.05) in the elderly and young subjects, respectively. 4 The recovery in the urine of metronidazole and its metabolites was 42 ± 21% and 87 ± 6% of dose in elderly and young subjects, respectively (P < 0.05). With this reservation the only elimination pathways of metronidazole affected by old age were the renal excretion of unchanged compound and the hydroxy metabolite. 5 It is concluded that the ability to eliminate metronidazole is preserved in old age and that age-related dose adjustments are not necessary.

scholarly journals Pharmacokinetic interaction between itraconazole and ceftriaxone in Yucatan miniature pigs.

1997 ◽  
Vol 41 (9) ◽  
pp. 2029-2032 ◽  
Author(s):  
A Cavalier ◽  
D Levêque ◽  
J D Peter ◽  
J Salmon ◽  
H Elkhaïli ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Pharmacokinetic Interaction ◽  
Time Curve ◽  
Miniature Pigs ◽  
Concentration Time ◽  
P Glycoprotein ◽  
Chronic Model ◽  
The Mean

Since ceftriaxone and itraconazole are highly protein bound, are excreted via a biliary pathway, and are in vitro modulators of the efflux pump P glycoprotein, a pharmacokinetic interaction between these antimicrobial agents can be hypothesized. Therefore, we evaluated the pharmacokinetics of itraconazole and ceftriaxone alone and in combination in a chronic model of catheterized miniature pigs. Itraconazole does not influence ceftriaxone kinetic behavior. The mean areas under the concentration-time curve (AUC) were 152.2 microg x h/ml (standard deviation [SD], 22.5) and 129.2 microg x h/ml (SD, 41.2) and the terminal half-lives were 1.1 h (SD, 0.3) and 0.9 h (SD, 0.2) when ceftriaxone was given alone and combined with itraconazole, respectively. Regarding itraconazole kinetics, ceftriaxone was shown to alter the disposition of the triazole. Contrary to what was expected, the AUC (from 0 to 8 h) decreased from 139.3 ng h/ml with itraconazole alone to 122.7 ng h/ml with itraconazole and ceftriaxone combined in pig 1, from 398.5 to 315.7 ng x h/ml in pig 2, and from 979.6 to 716.6 ng x h/ml in pig 3 (P of <0.01 by analysis of variance).

scholarly journals Distribution to the Brain and Protein Binding of 3′and 5-Substituted 2′,3′-Dideoxyuridine Derivatives, Studied by Microdialysis

1997 ◽  
Vol 8 (1) ◽  
pp. 47-53 ◽  
Author(s):  
N Borg ◽  
X-X Zhou ◽  
N-G Johansson ◽  
B Öberg ◽  
L Ståhle
Keyword(s):  
Protein Binding ◽  
Half Life ◽  
Partition Coefficients ◽  
Transport Mechanism ◽  
Chemical Properties ◽  
Peripheral Muscle ◽  
Pharmacokinetic Properties ◽  
The Brain

The aim of this study was to investigate a series of 3′ and 5-substituted 2′,3′-dideoxyuridine derivatives (ddUD) with respect to plasma protein binding, half-life and distribution across the blood-brain barrier in the rat. The microdialysis technique was used to study protein binding in human plasma ( in vitro), and to sample the extracellular space of rats with microdialysis probes implanted into the striatum of the brain and the gastrocnemic muscle ( in vivo). The compounds were analysed by HPLC with UV-detection. The octanol/water partition coefficients of the ddUD varied from 0.08-0.84. The protein binding of the ddUDs was approximately 80%. After s.c. administration (25 or 50 mg kg−1), the brain and muscle extracellular levels differed; brain levels were 0.18-0.36 of peripheral (muscle) concentrations. A multivariate analysis, which included data on zidovudine, alovudine and thymidine, demonstrated a relationship between the physicochemical and some of the pharmacokinetic properties of uridine analogues. The analysis shows that half-life and protein binding increases with decreasing p Ka. However, penetration to the brain is not correlated with the partition into octanol. It is concluded that the transport to the brain is not primarily dependent upon passive diffusion over a lipophilic barrier but, rather, to other chemical properties of the ddUDs. This is suggestive of a specific transport mechanism, e.g. the thymidine carrier.

scholarly journals Effect of Dosing Schedule on Pharmacokinetics of Alpha Interferon and Anti-Alpha Interferon Neutralizing Antibody in Mice

2001 ◽  
Vol 45 (1) ◽  
pp. 176-180 ◽  
Author(s):  
De-sheng Wang ◽  
Shigehiro Ohdo ◽  
Satoru Koyanagi ◽  
Hiroshi Takane ◽  
Hironori Aramaki ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Volume Of Distribution ◽  
Alpha Interferon ◽  
Male Mice ◽  
Time Curve ◽  
Dosing Schedule ◽  
Concentration Time ◽  
The Mean ◽  
Antibody Levels

ABSTRACT The influences of dosing time and dosing schedule on the plasma alpha interferon (IFN-α) concentration and the production of anti-IFN-α neutralizing antibodies were investigated in ICR male mice adapted to cycles of 12 h of light and 12 h of dark. In mice pretreated with IFN-α for 21 days, the plasma IFN-α concentrations were significantly lower than those in control mice (P< 0.01). The clearance of IFN-α and its volume of distribution obtained at steady state were significantly higher in the animals with IFN-α pretreatment than in the mice without IFN-α pretreatment. The area under the concentration-time curve and the mean residence time of IFN-α were significantly smaller in IFN-α-pretreated animals than in control animals. The plasma IFN-α levels (measured 2 h after dosing) were significantly lower in mice treated daily with IFN-α, while the anti-IFN-α neutralizing antibody levels (measured 24 h after dosing) were significantly increased on days 15 and 21 of treatment. Plasma IFN-α levels were significantly decreased in association with the production of anti-IFN-α neutralizing antibodies in mice treated with IFN-α daily at either 0900 or 2100 h. By contrast, the plasma IFN-α levels (measured 2 h after dosing) remained stable in mice treated with IFN-α at 0900 h on alternate days, while they were significantly lower after 21 days of treatment in mice treated with IFN-α at 2100 h on alternate days. These changes were associated with a significant increase in the levels of anti-IFN-α neutralizing antibodies in the latter group. The present findings suggest that an appropriate dosing schedule and/or dosing time for IFN-α may reduce the level of production of anti-IFN-α neutralizing antibodies in experimental and clinical situations.

scholarly journals Pharmacokinetics of the Novel Echinocandin CD101 in Multiple Animal Species

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Voon Ong ◽  
Kenneth D. James ◽  
Steven Smith ◽  
B. Radha Krishnan
Keyword(s):  
Cynomolgus Monkey ◽  
Half Life ◽  
Fungal Infections ◽  
Volume Of Distribution ◽  
The Novel ◽  
Time Curve ◽  
Content Type ◽  
Treatment And Prevention ◽  
The Mean ◽  
Rat Tissue

ABSTRACT CD101 is a novel semisynthetic echinocandin with antifungal activity against Candida and Aspergillus spp. The pharmacokinetics (PK) of CD101 administered intravenously to mice, rats, dogs, cynomolgus monkeys, and chimpanzees are presented. CD101 consistently exhibited very low clearance, a modest volume of distribution at steady state (V ss), and a long half-life (t 1/2) across all species tested. In mouse, rat, dog, cynomolgus monkey, and chimpanzee, CD101 clearance was 0.10, 0.47, 0.30, 0.41, and 0.06 ml/min/kg, respectively; V ss was 206, 1,390, not determined, 597, and 400 ml/kg, respectively; and t 1/2 was 25, 39, 53, 40, and 81 h, respectively. CD101 demonstrated a lower clearance and correspondingly longer half-life than those of anidulafungin, with more pronounced differences in higher species (anidulafungin t 1/2, 8 h in cynomolgus monkey and 30 h in chimpanzee). In the rat, tissue/plasma area under the concentration-time curve (AUC) ratios, in descending order, were 4.62 (kidney), 4.33 (lung), 4.14 (liver), 3.87 (spleen), 1.09 (heart), and 0.609 (brain), indicating that CD101 exposure relative to plasma levels was comparable for major organs (approximately 4-fold higher in tissue than in plasma), with the exception of the heart and brain. Biliary elimination of intact CD101 was the predominant route of excretion; the mean cumulative amount of CD101 excreted into the bile and feces over the course of 5 days accounted for 22.6% and 27.7% of the total dose administered, respectively. There were no sex differences in the pharmacokinetics of CD101. Given its low clearance, long half-life, and wide tissue distribution, CD101 once weekly is expected to provide appropriate systemic levels for treatment and prevention of invasive fungal infections.

scholarly journals Pharmacological Basis of CD101 Efficacy: Exposure Shape Matters

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Elizabeth A. Lakota ◽  
Justin C. Bader ◽  
Voon Ong ◽  
Ken Bartizal ◽  
Lynn Miesel ◽  
...  
Keyword(s):  
Time Course ◽  
Fungicidal Activity ◽  
Control Group ◽  
Time Curve ◽  
Content Type ◽  
Treatment Groups ◽  
Concentration Time ◽  
Treatment Control Group ◽  
Pharmacological Basis

ABSTRACT CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (∼133 h in humans, ∼70 to 80 h in mice). Given these characteristics, it is likely that the shape of the CD101 exposure (i.e., the time course of CD101 concentrations) influences efficacy. To test this hypothesis, doses which produce the same total area under the concentration-time curve (AUC) were administered to groups of neutropenic ICR mice infected with Candida albicans R303 using three different schedules. A total CD101 dose of 2 mg/kg was administered as a single intravenous (i.v.) dose or in equal divided doses of either 1 mg/kg twice weekly or 0.29 mg/kg/day over 7 days. The studies were performed using a murine disseminated candidiasis model. Animals were euthanized at 168 h following the start of treatment. Fungi grew well in the no-treatment control group and showed variable changes in fungal density in the treatment groups. When the CD101 AUC from 0 to 168 h (AUC0–168) was administered as a single dose, a >2 log10 CFU reduction from the baseline at 168 h was observed. When twice-weekly and daily regimens with similar AUC values were administered, net fungal stasis and a >1 log10 CFU increase from the baseline were observed, respectively. These data support the hypothesis that the shape of the CD101 AUC influences efficacy. Thus, CD101 administered once per week demonstrated a greater degree of fungal killing than the same dose divided into twice-weekly or daily regimens.

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