Postmortem Serum Protein Binding and Brain Concentrations of Antiepileptic Drugs in Autoptic Specimens from 45 Epileptic Patients

Rambeck, B.; Schnabel, Ralf; T, May; Jürgens, Uwe; Villagran, R

doi:10.1097/00007691-199011000-00004

Cited by 17 publications

(7 citation statements)

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“…Similar formulas were developed previously to estimate unbound concentrations of phenytoin and valproic acid, two antiepileptic drugs with high PPB (above 70%) based on plasma albumin concentrations (27,28), as total measured plasma concentrations could not always explain adverse events seen in patients (37)(38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients

Vanstraelen

Wauters

Vercammen

et al. 2014

Antimicrob Agents Chemother

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f Setting the adequate dose for voriconazole is challenging due to its variable pharmacokinetics. We investigated the impact of hypoalbuminemia (<35 g/liter) on voriconazole pharmacokinetics in adult intensive care unit (ICU) patients treated with voriconazole (20 samples in 13 patients) as well as in plasma samples from ICU patients that had been spiked with voriconazole at concentrations of 1.5 mg/liter, 2.9 mg/liter, and 9.0 mg/liter (66 samples from 22 patients). Plasma albumin concentrations ranged from 13.8 to 38.7 g/liter. Total voriconazole concentrations in adult ICU patients treated with voriconazole ranged from 0.5 to 8.7 mg/liter. Unbound and bound voriconazole concentrations were separated using high-throughput equilibrium dialysis followed by liquid chromatography-tandem mass spectrometry (LC-MSMS). Multivariate analysis revealed a positive relationship between voriconazole plasma protein binding and plasma albumin concentrations (P < 0.001), indicating higher unbound voriconazole concentrations with decreasing albumin concentrations. The correlation is more pronounced in the presence of elevated bilirubin concentrations (P ‫؍‬ 0.05). We therefore propose to adjust the measured total voriconazole concentrations in patients with abnormal plasma albumin and total serum bilirubin plasma concentrations who show adverse events potentially related to voriconazole via a formula that we developed. Assuming 50% protein binding on average and an upper limit of 5.5 mg/liter for total voriconazole concentrations, the upper limit for unbound voriconazole concentrations is 2.75 mg/liter. Alterations in voriconazole unbound concentrations caused by hypoalbuminemia and/or elevated bilirubin plasma concentrations cannot be countered immediately, due to the adult saturated hepatic metabolism. Consequently, increased unbound voriconazole concentrations can possibly cause adverse events, even when total voriconazole concentrations are within the reference range.

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Section: Discussionmentioning

confidence: 99%

Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients

Vanstraelen

Wauters

Vercammen

et al. 2014

Antimicrob Agents Chemother

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“…In the rodent brain, concentrations of CBZ at anticonvulsant doses are of the order of 10-50 ~tM (Masuda et al 1979); those of OCBZ or its metabolite and of LTG have not been published to our knowledge. In post-mortem brain tissue of patients under treatment at the time of death levels of 16-58 ~tM CBZ have been reported (Rambeck et al 1990). Thus, serum/plasma levels and/or brain concentrations of these compounds at doses at which seizures are controlled (and therefore comparable to the doses used in the present studies) are in or close to the concentration range in which Na ÷ channels and veratrine-induced GLU release are inhibited in vitro (Waldmeier et al 1995).…”

Section: Discussionmentioning

confidence: 99%

Effect of carbamazepine, oxcarbazepine and lamotrigine on the increase in extracellular glutamate elicited by veratridine in rat cortex and striatum

Waldmeier

Martin

Stöcklin

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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Lamotrigine, carbamazepine and oxcarbazepine inhibit veratrine-induced neurotransmitter release from rat brain slices in concentrations corresponding to those reached in plasma or brain in experimental animals or humans after anticonvulsant doses, presumably due to their sodium channel blocking properties. Microdialysis measurements of extracellular glutamate and aspartate were carried out in conscious rats in order to investigate whether corresponding effects occur in vivo Veratridine (10 microM) was applied via the perfusion medium to the cortex and the corpus striatum in the presence of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (1 mM in perfusion medium). Maximally effective anticonvulsant doses of carbamazepine (30 mg/kg), oxcarbazepine (60 mg/kg) and lamotrigine (15 mg/kg) were given orally. The uptake inhibitor increased extracellular glutamate and aspartate about 2-fold in striatum and about 7-fold and 3-fold, respectively, in cortex. Veratridine caused a further 2-3-fold increase in extracellular glutamate in striatum and cortex, respectively, but its effect on extracellular aspartate was less marked in both areas. None of the anticonvulsant compounds affected the veratridine-induced increases in extracellular glutamate or aspartate in the striatum which were, however, markedly inhibited by tetrodotoxin (1 microM) and thus are sensitive to sodium channel blockade. In the cortex the same drugs at the same doses did cause about 50% inhibition of the veratridine-induced increase in extracellular glutamate. Carbamazepine and to a lesser extent lamotrigine, but not oxcarbazepine, also inhibited the veratridine-induced increase in extracellular aspartate in the cortex. Although our results might seem to support the view that inhibition of glutamate and aspartate release is responsible for the anticonvulsant effects of lamotrigine, carbamazepine and oxcarbazepine, two complementary findings argue against this interpretation. First, as previously shown, inhibition of electrically induced released of glutamate requires 5 to 7 times higher concentrations of these compounds than release elicited by veratrine. Second, the present study indicates that doses totally suppressing convulsions caused no inhibition in the striatum and at best a 50% inhibition in the brain cortex. From this we conclude that the doses used here, although to some extent effective against veratridine, did not suppress the release of GLU and ASP elicited by the normal ongoing electrical activity of the glutamatergic and aspartatergic neurons and that the mechanism of the suppression of convulsions must be sought elsewhere.

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“…49 Only the free fraction is available to cross the blood-brain barrier, and the free serum concentration reflects the drug concentration in the central nervous system, where phenytoin exerts its action. 13,50,51 However, phenytoin is a substrate for efflux carriers of the blood-brain barrier. 45,52 Persistent subtherapeutic levels were reported in a patient with refractory epilepsy associated with overexpression of MDR1, which encodes the efflux carrier P-glycoprotein.…”

Section: Measurement Of Free Drugmentioning

confidence: 99%

“…4,49,[53][54][55] Case reports of critically ill patients with phenytoin toxicity showed that free phenytoin levels were disproportionally higher than values expected on the basis of total serum concentrations ( Table 4). [4][5][6][7]13 This was secondary to increased free phenytoin fractions. High free fractions in the serum raise concentrations in the brain.…”

Section: Measurement Of Free Drugmentioning

confidence: 99%

“…11,12 Case reports describe phenytoin toxicity secondary to inappropriate dosage adjustments based solely on total serum concentrations in patients with hypoalbuminemia. [4][5][6][7]13 A free trough phenytoin concentration should be obtained in the first 48-72 hours of therapy or when any seizure activity occurs. 14 Theoretical equations have been developed to correct reported total phenytoin serum concentrations when serum albumin levels are abnormal.…”

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confidence: 99%

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Therapeutic Drug Monitoring of Phenytoin in Critically Ill Patients

2008

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Therapeutic drug monitoring of phenytoin is necessary to ensure therapeutic and nontoxic levels. Hypoalbuminemia, renal failure, and interactions with other highly protein-bound drugs (e.g., valproic acid) alter protein binding of phenytoin. When these conditions are present, free serum concentrations, which represent the pharmacologically active entity, cannot be predicted from total serum concentrations. Besides general alterations in drug distribution and elimination, protein binding is often altered in critically ill patients. Case reports describe phenytoin toxicity secondary to inappropriate dosage adjustments based solely on total serum concentrations in patients with hypoalbuminemia. Free drug measurements and theoretical equations to facilitate the interpretation of total phenytoin serum levels have been introduced. However, they are not widely implemented in clinical practice because evidence of improvements in patient outcomes is limited. Knowledge of the pharmacokinetic properties of phenytoin is indispensable for correct interpretation of total serum concentrations when protein binding is altered. Free serum concentrations should be measured, or theoretically calculated if measurements are unavailable, to avoid misinterpretation of total serum levels and consequent inappropriate adjustments in the dosage of phenytoin in critically ill patients.

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Postmortem Serum Protein Binding and Brain Concentrations of Antiepileptic Drugs in Autoptic Specimens from 45 Epileptic Patients

Cited by 17 publications

References 0 publications

Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients

Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients

Effect of carbamazepine, oxcarbazepine and lamotrigine on the increase in extracellular glutamate elicited by veratridine in rat cortex and striatum

Therapeutic Drug Monitoring of Phenytoin in Critically Ill Patients

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