Pharmacokinetics of valproic acid in the elderly.

Perucca, Emilio; Grimaldi, Roberto; Gatti, G.; Pirracchio, S; Crema, Francesca; Frigo, G. M.

doi:10.1111/j.1365-2125.1984.tb02401.x

Cited by 92 publications

(49 citation statements)

References 11 publications

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“…Protein binding of valproic acid is significantly less in elderly than in young adults (Bauer et al 1985;Perucca et al 1984). The increase in free fraction is substantial; for example, Bauer et al (1985) report an average of 6.4% free valproic acid in young subjects (22 to 25 years) compared with 10.7% in elderly subjects (60 to 88 years).…”

Section: Valproic Acidmentioning

confidence: 94%

Plasma Protein Binding of Drugs in the Elderly

Wallace

Verbeeck

1987

Clinical Pharmacokinetics

121

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Binding to plasma proteins can affect the pharmacokinetics and pharmacodynamics of drugs. Age is one of many factors which can affect plasma protein binding of drugs. Unfortunately, very few generalities can be drawn from the studies of the effect of age on protein binding. Whether age has an effect on protein binding is dependent not only on the drug, but also on the manner in which the study is conducted. Several studies involve patients with various disease states making assessment of the effect of age alone on protein binding difficult. Results of different studies on the same drug do not always agree--in one case finding no change in protein binding with age and in another, a significant increase or decrease in protein binding. Most drugs which exhibit increased binding (decreased free fraction) in elderly subjects are basic and tend to have a greater affinity for alpha 1-acid glycoprotein than for albumin. The list of drugs exhibiting decreased binding (increased free fraction) in the elderly is longer and includes both acidic and basic drugs. The impact of changes in protein binding with age is dependent on the magnitude of the change, on the pharmacokinetic characteristics of the drug and on its therapeutic index. Some changes, although statistically significant, are not likely to be of importance clinically. From the studies reviewed, the free fraction is changed by greater than 50% in the elderly for only a few drugs, e.g. acetazolamide, diflunisal, etomidate, naproxen, salicylate, valproate and zimeldine.

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Section: Valproic Acidmentioning

confidence: 94%

Plasma Protein Binding of Drugs in the Elderly

Wallace

Verbeeck

1987

Clinical Pharmacokinetics

121

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“…Only a few small studies have compared the pharmacokinetics of valproic acid in younger and older patients [23][24][25]. In a study of steady-state valproate pharmacokinetics in six young adult and six elderly (66 to 72 years of age) volunteers, the average unbound fraction of valproate was 10.7% in the elderly compared with 6.4% in the younger volunteers.…”

Section: Valproic Acidmentioning

confidence: 97%

Epilepsy in the elderly

Leppik

2001

Curr Neurol Neurosci Rep

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The active prevalence rate of epilepsy among persons over 65 years of age is approximately 1.5%, about twice the rate in younger adults. Treatment of epilepsy in the elderly is complicated by alterations in drug metabolism, use of concomitant medications, and multiple medical problems. Drug interactions are a major issue, and a full knowledge of the isoenzyme profile and protein-binding characteristics of each drug (antiepileptic and other) must be known.

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“…It has been hypothesized that glucuronidation is generally unchanged in elderly population, despite a known decrease in liver mass (Greenblatt et al, 1991a,b). Altered drug clearance in the elderly can be attributed to changes in, e.g., liver mass, liver blood flow, and plasma protein binding (Perucca et al, 1984;Wynne et al, 1989;Fattore et al, 2006); however, these factors alone fail to explain the alteration in clearance observed in the elderly (Durnas et al, 1990).…”

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confidence: 99%

Effect of Aging on Glucuronidation of Valproic Acid in Human Liver Microsomes and the Role of UDP-Glucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10

Argikar

2008

Drug Metab Dispos

117

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ABSTRACT:Valproic acid (VPA) is a widely used anticonvulsant that is also approved for mood disorders, bipolar depression, and migraine. In vivo, valproate is metabolized oxidatively by cytochromes P450 and ␤-oxidation, as well as conjugatively via glucuronidation. The acyl glucuronide conjugate (valproate-glucuronide or VPAG) is the major urinary metabolite (30-50% of the dose). It has been hypothesized that glucuronidation of antiepileptic drugs is spared over age, despite a known decrease in liver mass. The formation rates of VPAG in a bank of elderly (65 years onward) human liver microsomes (HLMs) were measured by liquid chromatography/tandem mass spectrometry and compared with those in a younger (2-56 years) HLM bank. In vitro kinetic studies with recombinant UDPglucuronosyltransferases (UGTs) were completed. A 5-to 8-fold variation for the formation of VPAG was observed within the microsomal bank obtained from elderly and younger donors. VPAG formation ranged from 6.0 to 53.4 nmol/min/mg protein at 1 mM substrate concentration (n ‫؍‬ 36). The average velocities at 0.25, 0.5, and 1 mM VPA were 7.0, 13.4, and 25.4 nmol/min/mg protein, respectively, in the elderly HLM bank. Rates of VPAG formation were not significantly different in the HLM bank obtained from younger subjects. Intrinsic clearances (V max /K m ) for several cloned, expressed UGTs were determined. UGT1A4, UGT1A8, and UGT1A10 also were found to catalyze the formation of VPAG in vitro. This is the first reported activity of these UGTs toward VPA glucuronidation. UGT2B7 had the highest intrinsic clearance, whereas UGT1A1 demonstrated no activity. In conclusion, our investigation revealed no differences in VPAG formation in younger versus elderly HMLs and revealed three other UGTs that form VPAG in vitro.Glucuronidation is the conjugation of a glucuronic acid moiety to a range of functional groups-primary, secondary, tertiary, and aromatic amines, carboxylic acids, thiols, hydroxyls, and phenolic functional groups of xenobiotics or endogenous compounds. This conjugative reaction is carried out by UDP-glucuronosyltransferases (UGTs), enzymes expressed on the inner membrane of the endoplasmic reticulum (Dutton, 1966;Mackenzie et al., 1997;Remmel et al., 2008). Although predominantly expressed in the liver, UGTs are diverse in expression as well as function and are categorized into three subfamilies: UGT1A, UGT2A, and UGT2B (Mackenzie et al., 1997;Burchell et al., 1998;Tephly et al., 1998). Four UGT2B isoforms and nine UGT1A isoforms are expressed in humans and catalyze the glucuronidation of a variety of endogenous and exogenous substrates (Burchell et al., 1998;Mackenzie et al., 2000;Tukey and Strassburg, 2001). Glucuronidation is an important metabolic pathway for many drugs or oxidative metabolites. Several antiepileptic drugs (AEDs) including valproic acid (VPA) are excreted extensively as their glucuronides (Levy et al., 2002). VPA is directly glucuronidated to form its ester (acyl) glucuronide that is excreted in the urine, accounting for 30 -7...

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Pharmacokinetics of valproic acid in the elderly.

Cited by 92 publications

References 11 publications

Plasma Protein Binding of Drugs in the Elderly

Plasma Protein Binding of Drugs in the Elderly

Epilepsy in the elderly

Effect of Aging on Glucuronidation of Valproic Acid in Human Liver Microsomes and the Role of UDP-Glucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10

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