Diazepam plasma protein binding

BZDs also differ in their plasma protein binding capacity. The percentage of unbound oxazepam is 0.2% to 0.3%, diazepam 0% to 2%, of chlordiazepoxide 3% to 8%, and of lorazepam 7% to 12%. 

Routledge PA, Stargel WW, Kitchell BB, Barchowsky A, Shand DG. Sex-related differences in the plasma protein binding of lignocaine and diazepam. Br J Clin Pharmacol 1981 11 245-50. 

Viani A, Rizzo G, Carrai M et al. (1992). The effects of ageing on plasma albumin and plasma protein binding of diazepam, salicylic acid and digitoxin in healthy subjects and patients with renal impairment. Br J Clin Pharmacol, 33, 299-304. 

The plasma protein binding of diazepam is abont 97 to 99% in adults, regardless of age, but the distribution volnme of around 1 L/kg is higher in the elderly and females. Hypoalbuminemia leads to an increase in the fraction of unbonnd drug in plasma and a faster rate of elimination, as more drug is available for metabolism. 

The co-administration of carbamazepine can infrequently cause significant decreases in serum levels of some benzodiazepines (described with aiprazoiam and cionazepam). Vaiproate displaces diazepam from plasma protein binding and possibly inhibits its metabolism, leading to increased serum levels. A few studies have suggested that cbiordiazepoxide, cionazepam, and diazepam may elevate serum levels of pbenytoin. 

In healthy human subjects, a peak mean scrum concentration of 1607 p.g/liter was found 15 min after single bolus intravenous injections of 20 mg (Hilleslad etal.. 1974). A two-compartment open model has been used to describe elimination kinetics of diazepam in humans after single intravenous injections were reported (Andreasen etal., 1976 Klotz etal., 1975, 1976). A two-compartment open model has also been used to describe elimination kinetics of diazepam in experimental animals however, there were major interspccics differences in parameters such as r / and (Klotz etal., 1976), which indicated caution in the interpretation of animal studies. In human volunteers, the plasma protein binding of diazepam was greater than 95% (Klotz etal., 1976). The f /j of diazepam appears... 

It was conclusively shown that deoxychlordiazepoxide (393) had none of the phototoxic properties of the parent drug, at least in the rat [225]. Chlordiazepoxide, demethylchlordiazepoxide, demoxepam and diazepam-4-oxide were all phototoxic to a bacterial cell preparation. There was a close relationship between the phototoxicities of the A-oxides and the toxicity in the dark of their oxaziridines. The reduced forms of the four compounds were not phototoxic [ 228 ]. Kinetic studies demonstrated that the oxaziridine (390) covalently bonds to plasma proteins. The half-life of the oxaziridine in the presence of high concentrations of protein was about 30 min. It therefore has time not only to bind to biomolecules in the skin surface, but also to attack internal organs. This was put forward as the explanation of previously observed kidney and liver damage in the rat [229]. 

The availability of a chemical to the cells is affected by where it is stored. First, lipophilic chemicals tend to get absorbed by and retained in fat cells, from which they are released slowly back into the bloodstream. Second, some chemicals are strongly bound to plasma proteins and are released to the cells more slowly over time. For example, acetaminophen (Tylenol ) does not bind strongly to plasma proteins, while diazepam (Valium ) does. Thus, diazepam will persist in the body for longer periods of time than will acetaminophen. Finally, some elements, such as fluorine, lead, and strontium, are bound up in bone for long periods of time. As bone slowly renews itself or is broken down under special circumstances such as pregnancy, the chemicals are released and can affect the mother and fetus. 

Ultrafiltration has been used to determine the protein bound fraction of many drags, such as methadone (Wilkins et al. 1997), phenylacetate and phenylbu-tyrate (Boudoulas et al. 1996), etoposide (Robieux et al. 1997), doxorubicin and vincristine (Mayer and St-Onge 1995), disopyramide (Echize et al. 1995), and ketamine and its active metabolites (Hijazi and Boulieu 2002). Schumacher et al. (2000) have shown the applicability for the determination of erythro-cyte/plasma distribution. The method of UF has been applied in the measurement of free unaltered thyroxin or after displacement by salicylate as well after displacement by heparin in healthy people and in patients with non-thyroidal somatic illness (Faber et al. 1993). The protein binding of tritium labeled, antidiabetic repaglinide and its displacement by warfarin, furosemide, tolbutamide, diazepam, glibenclamide and nicardipine were determined by ultrafiltration (Plumetal. 2000). 

Protein Binding. In plasma, diazepam 98 to 99%, desmethyldiazepam about 97%. 

The use of vacutainer tubes and heparin was shown to alter the determination of protein binding. Heparin was shown to decrease the plasma binding of certain drugs including phenytoin, propranolol, lidocaine, diazepam, quinidine, and verapamil. This is also an in vitro artifact attributable to continued ex vivo activity of the lipoprotein lipase enzyme and accumulation of fatty acids in the blood collection tube. 

The benzodiazepines and their active metabolites bind to plasma proteins. The extent of binding correlates strongly with Upid solubility and ranges from about 70% for alprazolam to nearly 99% for diazepam. The concentration in the cerebrospinal fluid is approximately equal to the concentration of free drug in plasma. Competition with other protein-bound drugs may occur, but no clinically significant examples have been reported. 

PHARMACOKINETIC PROPERTIES Benzodiazepines are well absorbed orally, and peak plasma concentrations are usually reached within 1 hours. After intravenous administration, they redistribute in a manner typical of highly lipid-soluble agents (see Chapters 1 and 16). CNS effects develop rapidly but wane quickly as the drugs move to other tissues. Diazepam redistributes rapidly (fy of redistribution, -1 hour). The extent of binding of benzodiazepines to plasma proteins correlates with Upid solubriity, ranging from 99% for diazepam to -85% for clonazepam. 

Differences between males and females in the amount of free drug found in plasma, and of protein binding, have been reported for diazepam (Greenblatt et al, 1979 Abel et al, 1979) and for imipramine (Kristensen 1983). In the latter instance, a direct correlation was found with differences in lipoprotein and orosomucoid protein (1-a-acid glycoprotein) fractions (Greenblatt et al,... 

It was suggested that these changes occur because heparin displaces these drugs from their binding sites on the plasma albumins and that these changes in protein binding might possibly have some clinical consequences. For example, there could, theoretically, be sudden increases in sedation or respiratory depression because of the rapid increase in the active (free) fraction of diazepam. 

Uncertain. The suggestion is that diazepam may possibly alter the extent of the protein binding of digoxin within the plasma, which may have some influence on the renal tubular excretion, but see eomments on protein binding interactions in Drug distribution interactions , (p.3). The reason for the interaction between digoxin and alprazolam is not understood. 

Plasma levels increased to reach a steady state concentration in the range 100-150 ng/ml. Milk concentrations were more varied. In 2 mothers levels remained low with values for diazepam of 17-19 ng/ml and desmethyidiazepam 39-52 ng/ml. In the other 2 subjects the diazepam and desmethyidiazepam concentrations rose to 43 ng/ml and 85 ng/ml respectively. The higher concentrations of desmethyidiazepam in milk probably reflect reduced protein binding. Oxazepam was not found in the milk. It is calculated that if a nursing mother takes 10 mg/day of diazepam, then the infant will receive at the most 45 pg of active drug in 500 g of milk. 

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