Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid: Phenytoin

Lolin, Y. I.; Ratnaraj, Neville; Hjelm, M.; Patsalos, Philip N.

doi:10.1016/0920-1211(94)90020-5

Cited by 25 publications

(16 citation statements)

References 39 publications

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“…Necessarily, the penetration of drugs into the brain has to be highly regulated [61]. Most of the anticonvulsant or neuroleptic drugs used in therapy today belong to a group of drugs, which cross the blood-brain barrier mainly by diffusion or by the aid of drug transporter systems [15,[62][63][64][65]. Examples for such drugs are carbamazepine, phenytoin, phenobarbital, diazepam, and haloperidol.…”

Section: Localization and Function Of P450s At Brain's Barrier Regionmentioning

confidence: 99%

Expression and Function of Cytochrome P450 in Brain Drug Metabolism

Meyer¹,

Gehlhaus²,

Knoth³

et al. 2007

CDM

130

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Cytochrome P450 (CYP, P450) is the collective term for a superfamily of heme-containing membrane proteins responsible for the metabolism of approximately 70 - 80 % of clinically used drugs. Besides the liver and other peripheral organs, P450 isoforms are expressed in glial cells and neurons of the brain. To enlighten their function and significance is a topic of high interest, as most of the neuroactive drugs used in therapy today are not only substrates, but also inducers of brain P450s with far reaching consequences. First of all, brain P450s are regulated differentially from those in liver. The availability of the prosthetic heme group appears to be essential for correct membrane insertion and enzymatic functionality of brain P450s. Furthermore, although not contributing to body's overall drug metabolism, brain P450s fulfil particular functions within specific cell types of the brain. In astrocytes of brain's border lines P450 isoforms are expressed at very high level. They form a metabolic barrier regulating drugs' influx, modulate blood-flow regulation, and act as signalling enzymes in inflammation. In neurons, however, P450s apparently have different function. In specified brain regions such as hypothalamus, hippocampus and striatum they provide signalling molecules like steroids and fatty acids necessary for neuronal outgrowth and maintenance. Induction of these P450s by neuroactive drugs can alter steroid hormone signalling directly in drug target cells, which may cause clinically relevant side effects like reproductive disorders and sexual or mental dysfunction. The understanding of brain P450 function appears to be of major interest in long-term drug mediated therapy of neurological diseases.

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Section: Localization and Function Of P450s At Brain's Barrier Regionmentioning

confidence: 99%

Expression and Function of Cytochrome P450 in Brain Drug Metabolism

Meyer¹,

Gehlhaus²,

Knoth³

et al. 2007

CDM

130

View full text Add to dashboard Cite

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“…between the brain and serum (in c10 min) was also observed in other studies of intraperitoneally administered DZP (5 mgkg) in rats (43). The initial increase in the ratio of CSF to serum concentration above the ratio of free to total serum concentration may be explained if the hypothesis that the free serum drug concentration during the acute phase is exclusively the tissue-exchangeable drug concentration is incorrect; indeed, several studies have demonstrated that plasma protein-bound drug is often available for transport into the brain (10,(17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

“…developed to study the kinetics of drugs in these two compartments (10)(11)(12)(13)(14). Because of limited accessibility of CSF and the impracticability of repeated sampling in humans, no such human drug studies have been undertaken.…”

Section: C Walker Et Almentioning

confidence: 99%

Comparison of Single‐ and Repeated‐Dose Pharmacokinetics of Diazepam

et al. 1998

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Summary:Purpose: To determine whether repeat boluses of diazepam (DZP) lead to significant accumulation in the central nervous system and/or peripheral compartments, as repeat intravenous boluses of diazepam are commonly used in the treatment of status epilepticus (SE).Methods: In a rat model that permits simultaneous serum and cerebrospinal fluid (CSF) sampling, we characterized the pharmacokinetics of DZP and its metabolite, desmethyldiazepam, in CSF and blood using HPLC. DZP was administered by intraperitoneal injection as either a single dose (20 or 30 mg/ kg) or repeat doses (10 or 20 mgkg x 3, 1 h apart).Results: After a single intraperitoneal dose, DZP was rapidly absorbed with a time to maximum concentration of 10 min. The serum concentrations then declined biexponentially. DZP rapidly entered the CSF; the CSF to serum ratio reached equilibrium within 10 min, and was equivalent to the ratio of free to total serum concentration. Repeated DZP dosing resulted in a threefold decrease in volume of distribution and clearance (p < 0.001). This was reflected in the CSF concentration data; however, after the third dose, the ratio of CSF to serum concentration, also increased greatly, representing further persistence of DZP in the CSF compartment.Conclusions: Repeat dosing of DZP leads to substantial accumulation, and high, persistent serum and CSF concentrations, which may explain the toxic effects of repeat DZP dosing. Repeat dosing of DZP using a tapering protocol, however, may increase the effectiveness of DZP in treating SE by preventing relapses without substantially increasing toxicity.

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“…Despite this, chronic drug administration usually leads to multiple side effects, some of them are language and memory problems, psychiatric illness, and intellectual declines. The reason is that only a certain amount of the medication overcomes the hematoencephalic barrier and enters the brain, which requires its higher overall dosage . Taking this into account, an alternative in situ drug delivery represents another drug administration way that has excellent therapeutic benefits.…”

Section: Introductionmentioning

confidence: 99%

Effect of Thermal Treatment of Sol‐Gel Titania Reservoirs on Release Kinetics of Phenytoin

et al. 2012

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The thermal stability of antiepileptic drug phenytoin was investigated on its encapsulation in titania matrix. It was shown that the drug is stable up to 150°C, even though phenytoin melting point was previously reported to be much higher. The mechanism of phenytoin decomposition is suggested and confirmed by the experiment on heating to higher temperatures. The influence of thermal treatment on physicochemical parameters of the matrix was studied. Quite different drug release kinetics were obtained in vitro and discussed in terms of temperature treatment influence and interplay of parameters of the matrix.

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Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid: Phenytoin

Cited by 25 publications

References 39 publications

Expression and Function of Cytochrome P450 in Brain Drug Metabolism

Expression and Function of Cytochrome P450 in Brain Drug Metabolism

Comparison of Single‐ and Repeated‐Dose Pharmacokinetics of Diazepam

Effect of Thermal Treatment of Sol‐Gel Titania Reservoirs on Release Kinetics of Phenytoin

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