The displacing effect of a fatty acid on the binding of diazepam to human serum albumin

Diazepam is still one of the most used of the benzodiazepine group of drugs. Extensive studies over 10 years have defined a fairly complete profile of its kinetics. Minor aspects relating to patterns of its metabolism and excretion in certain age groups and in some disease states remain to be described quantitatively. However, there is more than sufficient kinetic information available for the requirements of good clinical practice. For optimum clinical benefit with minimum side-effects the following kinetic properties should be borne in mind: (a) there is a large interindividual variation (up to 30-fold) in dose/blood level ratios, especially when treatment is short-term; (b) the elimination half-life is prolonged in the elderly and the newborn and in some cases of liver disease; (c) there is accumulation of the active N-desmethylated metabolite during long-term treatment; and (d) administration of diazepam to pregnant women leads to rapid distribution from the maternal to fetal compartment: accumulation of both diazepam and desmethyldiazepam could cause prolonged sedation in the newborn. As there does not appear to be any clear relationship between the concentration of diazepam in the plasma and clinical effect, measurement of blood levels, other than for research purposes, is unnecessary. Based on kinetic data, a single administration of diazepam at night should be adequate for hypnotic and anxiolytic effects in most patients.

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“…Elevated serum free fatty acids do not modify the protein binding of diazepam (Tsutsumi et al, 1975).…”

Section: Hypoalbuminaemic Statesmentioning

confidence: 86%

Clinical Pharmacokinetics of Diazepam

Mandelli

Tognoni

Garattini

1978

Clinical Pharmacokinetics

442

107

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“…Heparin addition to plasma does not affect diazepam binding but addition of lauric acid (Tsutsumi et al, 1975) and stearic acid (Wong & Sellers, 1979) decreases binding to human serum. The latter workers also observed that palmitic acid addition to albumin at molar ratios less than unity enhanced diazepam binding to dilute human serum albumin solutions.…”

Section: Mahonmentioning

confidence: 89%

Sex‐related differences in the plasma protein binding of lignocaine and diazepam.

Routledge¹,

Stargel²,

Kitchell³

et al. 1981

Brit J Clinical Pharma

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1 The percentage of lignocaine free in the plasma of ten females receiving oral contraceptive medication was significantly greater than in 17 males of similar age (18-42 years). 2 In the same subjects the percentage of diazepam free in plasma was significantly greater in the contraceptive treated group than in 11 contraceptive-free females and significantly greater in contraceptive-free females than in males.3 The differences in lignocaine binding were almost completely attributable to changes in a,-acid glycoprotein concentration, which is reduced by oestrogens. The binding of diazepam was significantly related to albumin, a,-acid glycoprotein and non-esterified fatty acid concentrations which together were related to 55% of the variation in the binding of this basic compound.

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“…(1979) have shown that several benzodiazepines, halogenated derivatives of penicillin, antirheumatic drugs and tryptophan displace diazepam significantly from human serum albumin immobilised in microparticles of polyacrylamide (Sjoholm et al, 1979). Free fatty acids have also been shown to displace diazepam in vitro (Tsutsumi et al, 1975;Sjodin, 1977) and in vivo (Colburn & Gibaldi 1978; Wong & Sellers 1979;Sellers et al, 1980). Systemic administration of heparin, which increases non-esterified fatty acid concentration, also increases the unbound fraction of diazepam in subjects (Routledge et al, 1980).…”

Section: Introductionmentioning

confidence: 99%

Valproic acid and diazepam interaction in vivo.

Dhillon¹,

Richens²

1982

Brit J Clinical Pharma

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I The effect of oral administration of sodium valproate (1500 mg daily) on the distribution and elimination kinetics of intravenously administered diazepam in six healthy volunteers has been studied. 2 During valproate administration the unbound fraction of diazepam in serum increased approximately two fold. This was accompanied by a significant increase in apparent volume of distribution and plasma clearance of diazepam. 3 There was a positive correlation between the change in free fraction and the increase in both apparent volume of distribution and plasma clearance of the drug. 4 The concentration of unbound diazepam in serum (calculated from the percent free diazepam and total serum concentration) was significantly higher during valproate administration. Both the intrinsic clearance and volume of distribution of unbound drug were significantly reduced. 5 Mean serum N-desmethyldiazepam levels were significantly lower during valproate coadministration. 6 These results suggest that valproic acid displaces diazepam from plasma protein binding sites and inhibits its metabolism.

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The displacing effect of a fatty acid on the binding of diazepam to human serum albumin

Cited by 37 publications

References 4 publications

Clinical Pharmacokinetics of Diazepam

Clinical Pharmacokinetics of Diazepam

Sex‐related differences in the plasma protein binding of lignocaine and diazepam.

Valproic acid and diazepam interaction in vivo.

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