Oral Administration Of Phenytoin Research Articles

Pharmacokinetics of phenytoin and its metabolite, 4′‐HPPH, after intravenous and oral administration of phenytoin to diabetic rats induced by alloxan or streptozotocin

It has been reported that diabetic patients have an increased risk of developing epileptic convulsions compared with the non-diabetic population, and phenytoin has widely been used for neuralgia in diabetic neuropathy. It has also been reported that in both diabetic rats induced by alloxan (DMIA rats) and by streptozotocin (DMIS rats), the protein expression and mRNA level of 2C11 decreased, but in DMIS rats, the protein expression of CYP2C6 increased. Thus, the pharmacokinetics of phenytoin and 4'-HPPH were investigated after intravenous or oral administration of phenytoin at a dose of 25 mg/kg to DMIA and DMIS rats. After intravenous or oral administration of phenytoin, the AUC (or AUC(0-12 h)) values of both phenytoin and 4'-HPPH were comparable (not significantly different) between each diabetic and the respective control rats. Although the exact reason is not clear, this could have been due to opposite protein expression (and/or mRNA levels) of CYP2C6 and 2C11 in diabetic rats.

Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE

Axonal degeneration is a major contributor to non-remitting deficits in multiple sclerosis, and there is thus considerable current interest in the development of strategies that might prevent axonal loss in neuroinflammatory disease. Dysregulation of sodium ion homeostasis has been implicated in mechanisms leading to axonal degeneration, and several studies have shown that blockade of sodium channels can ameliorate axon damage following anoxic, traumatic and nitric oxide-induced CNS injury. Two sodium channel blockers, phenytoin and flecainide, have been reported to protect axons in experimental autoimmune encephalomyelitis (EAE) for 30 days, but long-term protective effects have not been studied. We demonstrate here that oral administration of phenytoin provides long-term (up to 180 days) protection for spinal cord corticospinal tract (CST) and dorsal column (DC) axons in both monophasic (C57/BL6 mice) and chronic-relapsing (Biozzi mice) murine EAE. Untreated C57/BL6 mice exhibit a 40-50% loss of CST and DF axons at 90 and 180 days post-EAE induction via myelin-oligodendrocyte glycoprotein (MOG) injection. In contrast, only 4% of DF axons are lost at 90 days, and only 8% are lost at 180 days in phenytoin-treated C57/BL6 mice with EAE; only 21-29% of CST axons are lost at 90 and 180 days in phenytoin-treated C57/BL6 mice with EAE. Attenuation of dorsal column compound action potentials was ameliorated and clinical status was also significantly enhanced with phenytoin treatment at 90 and 180 days in this model. In addition, inflammatory cell infiltration into the dorsal columns was reduced in phenytoin-treated mice with EAE compared with untreated mice with EAE. Similar results were obtained in Biozzi mice with chronic-relapsing EAE followed for 120 days post-injection. These observations demonstrate that phenytoin provides long-term protection of CNS axons and improves clinical status in both monophasic and chronic-relapsing models of neuroinflammation.

Effects of Paeoniae Radix, a traditional Chinese medicine, on the pharmacokinetics of phenytoin.

Phenytoin (PHT), one of the most widely prescribed antiepileptic drugs, has been reported to be associated with numerous drug-drug interactions. However, there are far fewer reports about the pharmacokinetic interactions between PHT and traditional Chinese medicines (TCMs). Paeoniae Radix (PR), one of the well-known TCMs, is used as an adjunct in some epileptic patients. In the present work, we studied the influences of PR on the pharmacokinetics of PHT in rats to identify the possible interactions between PR and PHT. A single dose of PHT (100 mg/kg) alone or in combination with PR extract (300 mg/kg) was administered by gavage to male SD rats. Serial blood samples of PHT were obtained for up to 24 h post-administration and measured by high-performance liquid-chromatography. The free (unbound) plasma concentrations of PHT were determined by fluorescence polarization immunoassay. The plasma concentrations were used to construct pharmacokinetic profiles by plotting drug concentration-time curves. All data were subsequently processed by the computer program WINNONLIN. Statistical comparisons of pharmacokinetic parameters were performed with the unpaired Student t-test. The mean maximum plasma concentration of PHT was attained 2 h after oral administration of PHT alone and 4-6 h after oral administration of PHT in combination with PR. The plasma level of PHT declined with a half-life of 5.38 h after PHT alone and 4.03 h after PHT and PR given together. No statistically significant differences were obtained in most of the pharmacokinetic parameters (Cmax, AUC, t1/2, MRT and CL/F) and protein binding rates of PHT between the two treatments. However, significant differences in Tmax and Vd/F between groups were noted. The significant increase in Tmax indicated that simultaneous oral administration of PR delayed the absorption of PHT. The delayed absorption of PHT might lead to its slow onset of clinical effect. There were no significant differences in Cmax, AUC, t1/2, MRT and CL/F of PHT between the two groups, showing that PR could not significantly affect the extent of absorption, metabolism and elimination of PHT. No significant difference in protein binding rate was found, indicating that PR might not significantly alter the protein binding of PHT. While a significant decrease in Vd/F was noted, the mechanism underlying the apparently decreased Vd/F of PHT influenced by PR needs further study.

Bioavailability and Anticonvulsant Activity of a Monoglyceride‐Derived Prodrug of Phenytoin after Oral Administration to Rats

The plasma levels of phenytoin after oral administration of phenytoin and phenytoin 2‐monoglyceride, a phenytoin prodrug, to rats were determined by gas chromatography. Compared to the application of the parent drug, administration of the prodrug resulted in a 3‐fold increase ofCmaxand a 4‐fold increase of the AUC. This correlated with an earlier onset and peaking of the anticonvulsant activity determined in the maximal electroshock (MES) test. The peak effect was reached 1h after dosing the monoglyceride compared to 2h after application of phenytoin itself. On the basis of the median effective dose, the prodrug was 3 times more effective antagonizing MES‐induced seizures than the parent drug. It is concluded that phenytoin 2‐monoglyceride might be a useful prodrug for the oral delivery of phenytoin.

Effects of phenytoin administration on murine immune function

The results obtained in these series of experiments indicate that oral administration of phenytoin (100, 50, or 25 mg/kg) to mice significantly depressed both humoral and cellular immune responses, evaluated by the techniques of enumeration of direct and indirect spleen plaque-forming cells (PFC) and the delayed-type hypersensitivity reaction (DTH) against sheep red blood cells (SR BC), when compared with those observed in normal control animals. Furthermore, spleen cells, purified splenic T lymphocytes or Ly 2 + T cells obtained from 100 mg/kg phenytoin-treated donor mice were capable of diminishing both PFC and DTH responses of normal cells transferred into lethally irradiated mice. The immunodepressor effect of phenytoin was observed despite the fact that administration of this drug induced a rise in spleen cellularity.

Sustained release of phenytoin following the oral administration of phenytoin sodium/ethylcellulose microcapsules in human subjects and rabbits.

Phenytoin sodium was microencapsulated with ethylcellulose (EC) by a coacervation-phase separation method from ethyl acetate solution to develop a prolonged release dosage form of phenytoin. Release of phenytoin from the microcapsules (phenytoin sodium/EC) was evaluated by the JP dissolution test in JP disintegration media No. 1 and No. 2. The release rates of phenytoin from phenytoin sodium powders were extremely rapid in both media, however, the release rates from the microcapsules were much more retarded. Following the oral administration of microcapsules to rabbits, prolonged plasma concentrations of phenytoin were obtained, while microcapsules orally administered to human subjects showed prolonged urinary excretion of phenytoin metabolites.

Neurotoxicity of phenytoin administered to newborn mice on developing cerebellum

To examine the neurotoxic effects of phenytoin (PHT) on cerebellar development, we administered 50 mg/kg PHT suspended in sesame oil orally to newborn Jcl:ICR mice once a day during postnatal days 2–14 and determined plasma PHT concentrations at designated intervals during the administration period. In the treated group, walking reflex and negative geotaxis were poorly developed on postnatal day 14. Pyknotic cells in the external granular layer (EGL) significantly increased and were prominent in the vermis area compared with controls on postnatal day 14. Plasma PHT levels were 34–36 μg/ml on the 3rd day of PHT treatment and approached a steady-state situation. Total brain weight, size of the cerebellum, and cerebellar weight were significantly reduced in the treated group on postnatal day 56. Accordingly, oral administration of PHT in the neonatal period induced neurotoxic damage on the developing cerebellum.

The effect of administration of phenytoin on the pharmacokinetics of isoxicam.

This study was designed to determine whether the disposition of isoxicam is influenced by the coadministration of another acidic drug, highly bound to plasma proteins and extensively metabolized, i.e., phenytoin. Ten healthy volunteers received an oral dose of 200 mg of isoxicam prior to and following the oral administration of phenytoin (100 mg) twice a day for 10 days. Eleven blood samples were drawn during the period following each dose of isoxicam. The area under the isoxicam plasma concentration-time curve (AUC infinity) increased from 389 +/- 66 to 464 +/- 62 micrograms h ml-1 (+/- SEM) (p less than 0.05) after treatment with phenytoin. This increase was due to an increase in isoxicam bioavailability; the absorption rate constant for isoxicam increased correspondingly from 0.34 +/- 0.06 to 1.16 +/- 0.38 h-1 (p less than 0.05). Distribution and clearance of isoxicam were probably not affected as its half-life was not changed, its plasma peak concentration increased, and the time to reach this peak decreased. It is concluded that phenytoin increases the rate and extent of absorption of isoxicam.

Correlation of serum phenytoin (diphenylhydantoin) with the administration of oral and intravenous phenytoin in dogs

The concentration of serum phenytoin was determined in normal dogs following the administration of phenytoin by either the intravenous or oral route. An intravenous dose of 11 and 33 mg/kg of body weight was given to six dogs and a further dose of 44 mg/kg was given to two dogs. Serial blood samples were taken following the three doses for determination of pharmacokinetic parameters. The mean half‐life was 3.35, 3.84 and 4.57 h as the dose was increased. Signs of toxicity occurred immediately following the infusion of phenytoin (emesis, ataxia and seizures). In the first oral studies, serial blood samples were taken for 2 consecutive days following a dose of 11 and 88 mg/kg, t.i.d. The time—concentration profiles of phenytoin varied significantly from one day to the next in the same dog. In the second oral study, blood samples were taken at 3 and 7 h following a dose of 11, 22, 44, 66 and 88 mg/kg, t.i.d. There was a poor correlation between the size of the oral dose and the concentration of serum phenytoin. Due to the short half‐life and poor absorption of phenytoin in dogs, it was concluded that the oral administration of phenytoin in dogs produces sub‐therapeutic and erratic serum concentrations of phenytoin which makes its efficacy as an anti‐convulsant questionable.

IMPAIRMENT OF INTESTINAL DECONJUGATION OF DIETARY FOLATE: A Possible Explanation of Megaloblastic Anæmia Associated with Phenytoin Therapy

Oral administration of phenytoin (diphenylhydantoin, ' Dilantin ', ' Epanutin ') impaired intestinal absorption of conjugated folate in some healthy volunteers but did not significantly affect the absorption of free folate. Phenytoin inhibited the in-vitro deconjugation of polyglutamic folate by homogenates of human intestinal mucosa. These observations suggest that the mechanism for the folate deficiency and megaloblastic anæmia which may accompany chronic anticonvulsant therapy may be inhibition of an enzyme or enzymes responsible for the intestinal deconjugation of folate sources in the diet.