Part I. In order to determine the effect of dose size on the bioavailability of phenytoin (Dilantinᴿ), a single intravenous dose of 15 mg/kg, single oral doses of 400, 800, 1600 mg, and 1600 mg in divided doses (i.e. 400 mg every three hours) were administered to six healthy male subjects. Values of V(max) and K(m) obtained from the intravenous dose were used to determine the extent of absorption from the oral doses. Although no statistically significant difference in extent of phenytoin absorption was observed, the time to reach maximum phenytoin serum concentrations increased significantly from 8.4 hours for the 400 mg dose and 13.2 hours for the 800 mg dose to 31.5 hours for the 1600 mg dose. Peak serum concentrations of 3.9, 5.7, 10.7, and 15.3 mg/1 were observed after the 400, 800, 1600 and 1600 mg divided doses, respectively. It is suggested that the prolonged, but complete, absorption of large phenytoin doses is due to a slow dissolution and continued absorption from the colon. Owing to the prolonged absorption of phenytoin, it may be necessary to use a larger oral than intravenous loading dose to produce similar maximum phenytoin serum concentrations. Part II. The effects of age and obesity on the pharmacokinetics of thiopental were studied in 7 morbidly obese (aged 25 to 46 years) and 22 lean patients (aged 25 to 83 years), who were primarily undergoing abdominal surgery. In all 29 patients, serum thiopental concentrations were determined by gas-liquid chromatography using a nitrogen-selective detector. Based upon total (bound+free) thiopental concentrations, the average (±S.E.) volumes of distribution (Vᵦ and V(ss)) were significantly larger in the obese (7.94 ± 1.72 1/kg and 4.72 ± 1.03 1/kg, respectively) than in the age-matched lean patients (1.95 ± 0.22 1/kg and 1.40 ± 0.16 1/kg, respectively). Clearance based on total thiopental concentrations normalized to total body weight (TBW) was not significantly different between the obese (0.18 ± 0.03 1/hr/kg) and lean patients (0.21 ± 0.02 1/hr/kg). However, total body clearance not normalized to TBW was significantly larger in the obese (24.98 ± 5.62 1/hr) than in the lean patients (11.86 ± 1.29 1/hr). The half-life of thiopental was significantly larger in the obese (31.87 ± 4.53 hours) than in the lean patients (6.61 ± 0.52 hours) and was primarily a function of the larger apparent volume of distribution for thiopental. The unbound fraction of thiopental in serum (range, 17.8% to 27.6%) did not depend on the degree of obesity, but was found to be greater with advancing age. The apparent volumes of distribution, Vᵦ and V(ss), were also related to age. No significant relationship was found between total body clearance with increasing age. Thus, the half-life of thiopental was positively correlated with age, and as in the obese study, was found to be primarily influenced by the apparent volume of distribution.

An investigation of the ratio of free to bound phenytoin in overdose cases was accomplished by three studies to answer these questions: 1. Will the free to bound ratio change with increasing total phenytoin concentration? 2. Will the free to bound ratio be altered with decreasing total protein concentration? 3. Do these results correlate with overdose cases? The results demonstrated that the ratio of free to bound phenytoin remains constant throughout the therapeutic range as long as a person has a normal total protein concentration. However, the free to bound ratio changes significantly when the total protein decreases by 25 per cent. This substantiates the importance of monitoring free and total phenytoin concentrations in hypoproteinemia.

Cerebral ischaemia, traumatic injury to the brain, inflammatory neurological disorders and HIV infections are amongst the most prevalent causes of neurodegeneration. Neuroprotective strategies are usually to limit the progressive secondary injury that generally occurs, thus limiting overall tissue damage. Neuroprotective strategies are usually to limit the progressive secondary injury that generally occurs, thus limiting overall tissue damage. Sodium channel blockers have been often used for this matter as they prevent the cascade of events culminating in free radical generation and eventually neuronal apoptosis. Newer compounds, such as antiperoxidants and free radical scavengers, show encouraging experimental results, but their clinical use is still very limited. Phenytoin being a popular drug in the treatment of epilepsy has also been used as a neuroprotectant during certain neurological emergencies and in pharmacological prophylaxis of post-traumatic epilepsy. Furthermore this agent functions by prolonging inactivation of voltage gated sodium channels. In these sets of experiment the neuroprotective properties of phenytoin were examined. The histological study revealed that phenytoin confers protection to the CA1 and CA3 regions of the hippocampus under the insult of QUIN. Cells maintain their characteristic shape and minimal tissue necrosis occurs in the presence of this agent. The in vitro effect of this antiepileptic drug on free radicals generation shows that phenytoin does not reduce or prevent the formation of these reactive species. Lipid peroxidation was induced using QUIN and iron (II), two known neurotoxins. The study reveals that only lipid peroxidation induced using iron (II) is reduced by phenytoin. These experiments were carried out in whole rat brain homogenate. These studies show that phenytoin possesses poor free radical scavenging properties. However, the dose-related reduction of iron-induced lipid peroxidation allows for speculation that phenytoin interacts with iron in order to reduce neuronal damage. Metal binding studies were performed using UV, IR and electrochemical analysis to examine the interaction of phenytoin with iron (II) and iron (III). Phenytoin, when added to iron (II) in solution, first oxidises the latter to iron (III) and maintains it in that form. A shift in the peak was observed in the UV spectrum when iron was added to phenytoin. Moreover, electrochemical studies indicate that the interaction between the metal and the ligand is very weak. The IR analysis it shows that phenytoin may be coordinating with iron through the Nitrogen atom on the phenytoin molecule. These studies show that phenytoin maintains iron in its oxidised form, which is a good property to possess as a neuroprotectants. Pineal organ culture showed that phenytoin does not increase melatonin production but slightly and non-significantly reduces the levels of this pineal hormone. However there is a significant rise in precursor NAS levels. As melatonin is known to possess antioxidant and free radical scavenging properties, this could mean that this drug can cause the CNS to become more susceptible to attacks by reactive oxygen species.

A study was made of the effects of diphenylhydantoin (DPH) and the carrier solution on the spleen, lymph node, and thymus. DPH was injected i.p. at concentrations of 5 and 10 mg./100 gm. for 30 and 60 days. Hematologic effects observed were leucocytosis, neutrophilia, eosinophilia, and lymphopenia. Respiratory measurements of lymph node tissue slices were made using the oxygen electrode method. The carrier solution was found to cause a marked increase in oxygen consumption. A DPH effect on lymph tissue respiration was not observed. The carrier alone caused an atrophy of the lymph nodes and thymus, as well as an increase in the total body weight. Histological examination revealed that the 5 mg./100 gm. DPH injected for 60 days and the 10 mg./100 gm. DPH injected for 30 or 60 days produced a histiocytic cell type lymphoma, resembling Hodgkin's disease in the lymph node, thymus, and spleen in rats. The data indicated that DPH may not be a direct carcinogen, but it may interfere with the normal immune mechanism to produce the changes observed.