The Effect of Age on the Pharmacokinetics of Diazepam

1980 ◽  
Vol 59 (6) ◽  
pp. 479-483 ◽  
Author(s):  
A. F. MacKlon ◽  
M. Barton ◽  
O. James ◽  
M. D. Rawlins
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Half Life ◽  
Free Fraction ◽  
The Elderly ◽  
Total Plasma ◽  
Increased Sensitivity ◽  
Plasma Half Life ◽  
Effect Of Age

1. After intravenous administration to 19 subjects, aged 18–95 years, plasma diazepam concentrations were measured over 160 h. Plasma protein binding of diazepam was also measured in each subject. 2. The terminal plasma half-life of diazepam ranged from 15.0 to 125 h and was positively correlated with age (r = 0.797). Total plasma diazepam clearance was not correlated with age (r = −0.017). 3. The free fraction of diazepam ranged from 0.0137 to 0.0386 and was significantly correlated with age (r = +0.863). Free diazepam clearance, which ranged from 432 to 1870 ml/min, was also correlated with age (r = −0.717). 4. It is concluded that the increased sensitivity of the elderly to diazepam is, at least in part, due to pharmacokinetic factors.

Effects of pronounced haemodilution on the plasma protein binding of lidocaine

Perfusion ◽  
1995 ◽  
Vol 10 (1) ◽  
pp. 17-20 ◽  
Author(s):  
PA Lönnqvist ◽  
L. Herngren
Keyword(s):  
Plasma Concentration ◽  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Free Fraction ◽  
Total Plasma ◽  
Free Concentration ◽  
Significant Difference ◽  
Total Plasma Concentration ◽  
Pharmacologically Active

The effects of pronounced haemodilution on the protein binding of lidocaine was investigated in vitro in plasma from five healthy adult volunteers. The plasma was diluted with a phosphate buffer to reach a plasma protein concentration normally seen during paediatric cardiopulmonary bypass (CPB) and protein binding was determined at a low (1.5 μg/ml) and a moderate (4 μg/ml) total plasma concentration of lidocaine. The effects of different haematocrits on plasma protein binding was also determined over the haematocrit range 20-60%. The binding of lidocaine was found to be inversely related to the degree of dilution, i.e. the free fraction increased significantly with increasing dilution (p < 0.0001). Furthermore, the binding was dependent on the total plasma concentration of lidocaine, since a significantly higher percentage of free drug was found at the higher total lidocaine level (4 μg/ml) compared with the lower level (1.5 μg/ml) (p < 0.05). No significant difference in the free fraction of lidocaine could be found over the studied haematocrit range. The results of the present study indicate that plasma protein levels commonly associated with CPB in neonates and infants are associated with a significant increase in the free, unbound and pharmacologically active fraction of lidocaine compared with normal conditions. The use of commonly recommended dosages of lidocaine might result in toxic-free concentration in this setting.

Apparent Valproic Acid Neurotoxicity in a Hypoalbuminemic Patient

1993 ◽  
Vol 27 (1) ◽  
pp. 32-35 ◽  
Author(s):  
Barry E. Gidal ◽  
D. Michael Collins ◽  
Brad R. Beinlich
Keyword(s):  
Valproic Acid ◽  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Plasma Concentrations ◽  
Free Fraction ◽  
Laboratory Evaluation ◽  
Neurologic Symptoms ◽  
Drug Concentrations ◽  
Dependent Protein

OBJECTIVE: To report a case of possible neurotoxicity caused by markedly elevated free valproic acid (VPA) plasma concentrations. CASE SUMMARY: A patient with a history of a mixed-type seizure disorder that had been treated with oral VPA 1000 mg four times daily for the previous two years was admitted to the neurology service with the chief complaint of increasing difficulty in walking and involuntary muscle jerks that were new in onset. The patient was hypersomnolent and dysarthric. The total plasma VPA concentration was 103 μg/mL, which was only slightly above the recommended therapeutic range (50–100 μg/mL). VPA free fraction and free plasma concentrations, however, were unexpectedly elevated (26 percent, 26.8 μg/mL, respectively). Further laboratory evaluation revealed a serum albumin concentration of 33 g/L. The neurologic symptoms resolved upon VPA dosage reduction. DISCUSSION: VPA displays concentration-dependent protein binding, resulting in disproportionate increases in drug free fraction with increasing drug concentration. This effect may be magnified in patients with decreased plasma protein-binding capacity. The plasma protein-binding kinetics of VPA are reviewed and the implications for therapeutic drug monitoring are discussed. CONCLUSIONS: It is likely that the markedly elevated free VPA plasma concentrations contributed to the neurologic symptoms displayed in this patient. In patients with decreased albumin concentrations, failure to recognize concentration-dependent protein binding, as well as exclusive reliance upon total drug concentrations, may lead to erroneous pharmacokinetic and therapeutic interpretations.

scholarly journals Pharmacokinetics, Tissue Distribution, Plasma Protein Binding Studies of 10-Dehydroxyl-12-Demethoxy-Conophylline, a Novel Anti-Tumor Candidate, in Rats

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 283
Author(s):  
Chengjun Jiang ◽  
Jie Li ◽  
Xianghai Cai ◽  
Nini Li ◽  
Yan Guo ◽  
...  
Keyword(s):  
Protein Binding ◽  
Tissue Distribution ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Equilibrium Dialysis ◽  
Free Fraction ◽  
Ultra Performance Liquid Chromatography ◽  
Sprague Dawley ◽  
Binding Studies ◽  
High Protein Binding

10-Dehydroxyl-12-demethoxy-conophylline is a natural anticancer candidate. The motivation of this study was to explore the pharmacokinetic profiles, tissue distribution, and plasma protein binding of 10-dehydroxyl-12-demethoxy-conophylline in Sprague Dawley rats. A rapid, sensitive, and specific ultra-performance liquid chromatography (UPLC) system with a fluorescence (FLR) detection method was developed for the determination of 10-dehydroxyl-12-demethoxy-conophylline in different rat biological samples. After intravenous (i.v.) dosing of 10-dehydroxyl-12-demethoxy-conophylline at different levels (4, 8, and 12 mg/kg), the half-life t1/2α of intravenous administration was about 7 min and the t1/2β was about 68 min. The AUC0→∞ increased in a dose-proportional manner from 68.478 μg/L·min for 4 mg/kg to 305.616 mg/L·min for 12 mg/kg. After intragastrical (i.g.) dosing of 20 mg/kg, plasma levels of 10-dehydroxyl-12-demethoxy-conophylline peaked at about 90 min. 10-dehydroxyl-12-demethoxy-conophyllinea absolute oral bioavailability was only 15.79%. The pharmacokinetics process of the drug was fit to a two-room model. Following a single i.v. dose (8 mg/kg), 10-dehydroxyl-12-demethoxy-conophylline was detected in all examined tissues with the highest in kidney, liver, and lung. Equilibrium dialysis was used to evaluate plasma protein binding of 10-dehydroxyl-12-demethoxy-conophylline at three concentrations (1.00, 2.50, and 5.00 µg/mL). Results indicated a very high protein binding degree (over 80%), reducing substantially the free fraction of the compound.

scholarly journals Effect of age on plasma protein binding of several veterinary drugs in dairy calves 2

2018 ◽  
Vol 121 ◽  
pp. 59-64 ◽  
Author(s):  
Danielle A. Mzyk ◽  
Claire M. Bublitz ◽  
Ginger D. Hobgood ◽  
Marilyn N. Martinez ◽  
Jennifer L. Davis ◽  
...  
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Veterinary Drugs ◽  
Dairy Calves ◽  
Effect Of Age
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