Identifying patients who might benefit from free phenytoin monitoring

Guidelines for measuring free drug concentrations in serum have become necessary due to the easy availability of these assays as a result of the introduction of commercial kits. The present study was performed to identify patients or groups of patients in whom the serum free phenytoin fraction varied from normal, such that they might benefit from measurement of serum free phenytoin. Three hundred fourteen samples submitted for routine phenytoin analysis were studied by enzyme-modified immunoassay technique (EMIT). Thirty-eight patients on phenytoin monotherapy and without other factors thought to affect protein binding of this drug had a mean (+/- SD) free phenytoin fraction of 9.8 +/- 1.8% of total concentration (mean serum albumin concentration 43.4 +/- 3.9 g/L). The free fraction was elevated by administration of comedications which are themselves highly protein bound, and in those patients who were hypoalbuminaemic (serum albumin less than 30 g/L). The groups studied were not mutually exclusive, but stepwise regression analysis showed that other factors known to affect serum albumin (e.g., age greater than 65 years, liver or renal disease, or pregnancy) did not, in themselves, produce a significant effect on free phenytoin fraction. Similarly, an elevated total serum phenytoin concentration was not a significant factor in producing an elevation in free phenytoin fraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Should we routinely measure free plasma phenytoin concentration?

The plasma protein binding of phenytoin was investigated in 56 epileptic patients attending the outpatient clinic. The free phenytoin fraction was measured by equilibrium dialysis at 37 degrees C and the total concentration by a homogenous enzyme immunoassay technique. The free fraction ranged from 0.123 to 0.177 (median 0.144, mean +/- s.d. = 0.145 +/- 0.12). Distribution was consistent with normality. Four of the patients were also taking sodium valproate. The median free fraction of phenytoin in these patients was 0.174, 21% higher than that of the total group (P less than 0.05). The total concentration of phenytoin varied from 0.3 to 29.4 micrograms/ml (median 12 micrograms/ml, mean +/- s.d. = 13.31 +/- 6.13 micrograms/ml) and the free fraction was not related to the total drug concentration. There was a highly significant relationship between free phenytoin concentration and total phenytoin concentration (r = 0.986, P less than 0.001). There appears to be very little variability in protein binding of phenytoin in epileptic patients and thus total plasma phenytoin concentration closely reflects the free (unbound) drug concentration. Routine estimation of free plasma phenytoin concentration is therefore unnecessary and should be reserved for those patients where alteration in binding is likely, e.g. renal or hepatic disease or where adverse effects occur at unexpectedly low total phenytoin concentrations.     

Effect of valproate on free plasma phenytoin concentrations.

The plasma protein binding of phenytoin was studied in nine epileptic patients before and during addition of sodium valproate to the drug therapy. The free phenytoin fraction in plasma was significantly greater during sodium valproate treatment. The mean free fraction rose from 0.135 +/- 0.019 (s.d.) to 0.182 +/- 0.030. Total plasma phenytoin concentration fell significantly from a range of 4.3-26.2 micrograms/ml to 3.4-19.8 micrograms/ml during sodium valproate treatment. Neither the free plasma concentration nor the saliva concentration of phenytoin was significantly altered by sodium valproate. No significant correlation was found between plasma valproic acid concentrations and the change in phenytoin binding. We conclude that valproic acid displaces phenytoin from plasma protein binding sites but does not inhibit its metabolism.     

Effect of hypercapnia and/or hypoxemia and metabolic acidosis on kinetics and concentrations of phenytoin in the cerebrospinal fluid of conscious rabbits

The present study was designed to determine the effect of changes in gases and pH in the blood on kinetics and passage to the cerebrospinal fluid (CSF) of phenytoin (DPH). Five groups of 6 rabbits were used, a control [with a mean partial pressure (Pa) of oxygen of 84 +/- 2 (SEM) mmHg, partial pressure of carbon dioxide (PaCO2) of 23 +/- 1 mmHg and pH = 7.512 +/- 0.018], a second group with hypercapnia (PaCO2 = 65 +/- 3 mmHg, pH = 7.244 +/- 0.008), a third group with hypoxemia (PaO2 = 48 +/- 2 mmHg), a fourth group with hypercapnia combined with hypoxemia (PaCO2 = 72 +/- 3 mmHg, PaO2 = 51 +/- 1 mmHg and pH = 7.252 +/- 0.008) and a fifth group with metabolic acidosis (pH = 7.232 +/- 0.011). All animals were conscious during the experiments following the administration of 10 mg/kg (i.v.) of phenytoin, hypoxemia decreased the clearance of phenytoin from 4.20 +/- 0.55 to 2.65 +/- 0.44 ml/min per kg (P less than 0.05) and consequently the area under the plasma concentration/time curve (AUC) for phenytoin increased (2575 +/- 319 to 4316 +/- 740 micrograms min/ml; P less than 0.05). Metabolic acidosis increased the volume of distribution of phenytoin from 780 +/- 70 to 1103 +/- 65 ml/kg (P less than 0.01). The protein binding of phenytoin was not affected by any of the experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of glycated albumin on phenytoin binding in elderly patients with type II diabetes mellitus

We evaluated the effect of glycated albumin on phenytoin protein binding in 36 elderly (age range 63-94 yrs) patients with type II diabetes mellitus (DM) under diet management. Serum was spiked with 15 mg/L phenytoin and incubated. A serum ultrafiltrate was obtained from each sample for determining total and free phenytoin concentrations. Glycated hemoglobin was determined by boronate-affinity chromatography, and glycated albumin was separated from nonglycated fractions with boronate-agarose gel. Glycated hemoglobin in the study group ranged from 4.3-14.6% (mean 7.8 +/- SD 2.1%) and glycated albumin ranged from 3.7-12.5% (7.4 +/- SD 2.6%). We observed no correlation between glycated albumin and the percentage of free phenytoin (r2 = -0.14; p = 0.419). The concentration of nonglycated albumin ranged from 0.66-4.28 g/dl (mean 3.45 +/- 0.67 g/dl) and was calculated from measured total and glycated albumin concentrations. A correlation between the free fraction of phenytoin and nonglycated albumin was not demonstrated (r2 = 0.22, p = 0.22). In addition, a correlation was not observed between total glycated albumin and the free fraction of phenytoin (r2 = -0.095; p = 0.58). We conclude that elderly patients with type II DM under diet control do not have significant alterations in phenytoin protein binding. The use of total serum phenytoin levels therefore appears appropriate for determining phenytoin dosages in elderly patients with well controlled type II DM.     

Cimetidine-phenytoin interaction: Effect on serum phenytoin concentration and antipyrine test

Summary In a prospective study in nine patients the effects of phenytoin and of cimetidine (1000mg/day) + phenytoin on the antipyrine test and serum phenytoin concentrations were studied. Serum phenytoin increased from the steady state level of 5.7±1.3 mg/l to 9.1±1.4mg/l after three weeks on cimetidine (p<0.01), and fell to 5.8±1.2 mg/l within two weeks after withdrawal of cimetidine. The protein binding of phenytoin was not changed by cimetidine. After use of phenytoin for 2–4 months, antipyrine clearance increased from 0.67±0.06ml/min/kg to 1.61±0.22 ml/ min/kg, and antipyrine half-live fell from 10.9±1.3h to 4.5±0.6h as compared to the values before phenytoin treatment (p<0.01). After three weeks combined use of cimetidine and phenytoin, antipyrine clearance was decreased to 1.01±0.07 ml/min/kg and antipyrine half-life was prolonged to 6.1±0.5h, (p<0.01) compared to the values on phenytoin alone. The distribution volume of antipyrine was not affected by phenytoin nor by cimetidine + phenytoin. The half-life of cimetidine was 2.8±0.3h in the patients on longterm phenytoin treatment. There was a significant positive correlation (p<0.001) between the increase in serum phenytoin concentration and the prolongation of antipyrine half-life caused by cimetidine. Thus, cimetidine increases serum phenytoin concentration, very probably by inhibiting its metabolism. Care should be taken in the concomitant use of cimetidine and phenytoin, and the dose of phenytoin should be modified according to the clinical symptoms and serum phenytoin concentrations.Part of this work was presented at the Joint Meeting of the Scandinavian and German Pharmacological Societies, September 1980 [14]     

高效液相色谱法同时测定苯巴比妥、苯妥英、卡马西平的血药浓度

目的:建立以高效液相色谱法同时测定苯巴比妥、苯妥英、卡马西平血药浓度的方法。方法:取患者血清,经二氯甲烷提取后在C18柱上分析,流动相为甲醇-水(57:43),柱温为30℃,检测波长为254nm,流速为0.8ml/min。结果:苯巴比妥、苯妥英、卡马西平分别在2.5-40、2.5-40、1.25-20μg/ml范围内线性关系良好,日内和日间RSD<10％(n=5)。结论:本方法简便、稳定,用于苯巴比妥、苯妥英、卡马西平的血药浓度监测效果良好。     

Efficacy of individualized phenytoin sodium loading doses administered by intravenous infusion

The safety and efficacy of administering individualized phenytoin sodium loading doses by intravenous infusion were studied on 40 occasions in 37 adult patients having seizures. Doses were calculated based on an average volume of distribution (0.75 L/kg) and desired plasma phenytoin concentration. Total and free phenytoin concentrations were determined before and after the infusion. Phenytoin sodium doses of 225-1300 mg were administered by intravenous infusion at a rate of 40 mg/min after dilution in 0.9% sodium chloride injection to concentrations ranging from 4.5 to 13.5 mg/mL. Infusion rates were reduced if adverse effects occurred. The dosing method accurately achieved desired phenytoin concentrations (predicted mean +/- S.D. concentration, 18.3 +/- 1.6 micrograms/mL; observed mean concentration, 17.4 +/- 2.5 micrograms/mL). Postinfusion concentrations of free phenytoin ranged from 0.8 to 3.6 micrograms/mL (mean +/- S.D., 1.7 +/- 0.6 micrograms/mL). Of 21 patients evaluated for efficacy, 16 responded. A total of 45% of patients experienced pain at the infusion site, which diminished when the infusion rate was reduced. No serious cardiovascular or neurological toxicities occurred. The intravenous infusion method of administration is safe and effective and is useful for rapid achievement of therapeutic phenytoin concentrations in the emergency room setting.     

Pharmacokinetics of ceftriaxone in subjects with renal insufficiency

The pharmacokinetics of ceftriaxone was studied in 14 men and women volunteers with renal insufficiency. Subjects were grouped by renal function: those with end-stage renal disease (CLcr less than 15 mL/min/1.73 sq m) but not receiving dialysis, those with severe renal insufficiency (CLcr 16-30 mL/min/1.73 sq m), and those with moderate renal insufficiency (CLcr 31-60 mL/min/1.73 sq m). Ceftriaxone 1 g as the sodium salt was administered by i.v. infusion over 30 minutes, and blood and urine samples were collected before and up to 48 hours after drug administration. The pharmacokinetic data were described using a nonlinear least-squares computer program. For volunteers with a creatinine clearance of less than 15 mL/min/1.73 sq m, the mean half-life was 15.6 hours. For subjects with a creatinine clearance of 31-60 mL/min/1.73 sq m, the mean half-life was 11.9 hours. Plasma ceftriaxone concentrations measured at the conclusion of the infusion (mean peak concentration 122 +/- 53.1 micrograms/mL) or 24 hours after the infusion (mean concentration 20.2 +/- 6.14 micrograms/mL) were similar in each study group. A dose of ceftriaxone 1 g every 24 hours in patients with renal insufficiency is probably adequate for inhibiting most susceptible gram-positive and gram-negative microorganisms.     

The effect of sucralfate on the steady-state serum concentrations of phenytoin

The effect of sucralfate on steady-state phenytoin concentrations was evaluated in 6 normal volunteers. The subjects took phenytoin at bedtime until steady-state was confirmed (8 to 9 days) and then took in addition sucralfate 1g four times daily for a further 7 days. Serum phenytoin concentrations were measured on days 1, 3, and 7 of sucralfate administration. Measured phenytoin concentrations were 10.9 +/- 3.0 mcg/ml and 11.0 +/- 3.1 mcg/ml before sucralfate and 10.8 +/- 3.1 mcg/ml, 11.4 +/- 3.2 mcg/ml, and 11.1 +/- 2.5 mcg/ml during sucralfate administration (p greater than 0.05; ANOVA). These results suggest there is not a significant drug interaction between sucralfate and phenytoin.     

Therapeutic blood levels of phenytoin in treatment of paroxysmal choreoathetosis

Eight patients with paroxysmal choreoathetosis received phenytoin therapy, starting from 50 mg of oral phenytoin with a gradual increment of the dose. After successful control of the paroxysmal attacks, blood levels of phenytoin in these patients were measured by enzyme immunoassay. The mean phenytoin blood level was 5.2 +/- 3.2 micrograms/ml, with a range of 1.1-10.9 micrograms/ml. It is proposed that phenytoin can be maintained at a lower level in the treatment of paroxysmal choreoathetosis than in seizure control.     

高效液相色谱法测定苯巴比妥、苯妥英、卡马西平的血药浓度

目的 :建立 HPL C法测定抗癫药苯巴比妥 (PB)、苯妥英 (PT)、卡马西平 (CBZ)的血药浓度。方法 :反相柱 ODS- Hy-persil(4.6 m m× 10 0 mm ,5︼m ) ,流动相为甲醇∶水 (5 2∶ 48) ,流速 0 .8m l/ m in,紫外检测波长 2 5 4nm ,以上 3药互为内标。标本经 CH2 Cl2 提取 ,蒸干后用流动相重溶进样。结果 :PB、PT、CBZ的保留时间分别为 3.2 2、5 .5 7、6 .80 m in;最低检测浓度分别为 0 .2 5、0 .5、0 .0 5︼g/ m l;线性范围分别为 2 .5～ 40、2 .5～ 40、1.2 5～ 2 0︼g/ ml;相对回收率分别为 10 1.49%、10 4.19%、98.70 % ;日内 RSD分别为 1.81%、5 .94%、1.81% ;日间 RSD分别为 6 .0 6 %、3.35 %、3.96 %。结论 :本法具快速、灵敏、实用等优点。     

Pharmacokinetics and clinical effects of phenytoin and fosphenytoin in children with severe malaria and status epilepticus

AIMS: Status epilepticus is common in children with severe falciparum malaria and is associated with poor outcome. Phenytoin is often used to control status epilepticus, but its water-soluble prodrug, fosphenytoin, may be more useful as it is easier to administer. We studied the pharmacokinetics and clinical effects of phenytoin and fosphenytoin sodium in children with severe falciparum malaria and status epilepticus. METHODS: Children received intravenous (i.v.) phenytoin as a 18 mg kg-1 loading dose infused over 20 min followed by a 2.5 mg x kg(-1) 12 hourly maintenance dose infused over 5 min (n = 11), or i.v. fosphenytoin, administered at a rate of 50 mg x min(-1) phenytoin sodium equivalents (PE; n = 16), or intramuscular (i.m.) fosphenytoin as a 18 mg x kg(-1) loading dose followed by 2.5 mg x kg(-1) 12 hourly of PE (n = 11). Concentrations of phenytoin in plasma and cerebrospinal fluid (CSF), frequency of seizures, cardiovascular effects (respiratory rate, blood pressure, trancutaneous oxygen tension and level of consciousness) and middle cerebral artery (MCA) blood flow velocity were monitored. RESULTS: After all routes of administration, a plasma unbound phenytoin concentration of more than 1 microg x ml(-1) was rapidly (within 5-20 min) attained. Mean (95% confidence interval) steady state free phenytoin concentrations were 2.1 (1.7, 2.4; i.v. phenytoin, n = 6), 1.5 (0.96, 2.1; i.v. fosphenytoin, n = 11) and 1.4 (0.5, 2.4; i.m. fosphenytoin, n = 6), and were not statistically different for the three routes of administration. Median times (range) to peak plasma phenytoin concentrations following the loading dose were 0.08 (0.08-0.17), 0.37 (0.33-0.67) and 0.38 (0.17-2.0) h for i.v. fosphenytoin, i.v. phenytoin and i.m. fosphenytoin, respectively. CSF: plasma phenytoin concentration ratio ranged from 0.12 to 0.53 (median = 0.28, n = 16). Status epilepticus was controlled in only 36% (4/11) following i.v. phenytoin, 44% (7/16), following i.v. fosphenytoin and 64% (7/11) following i.m. fosphenytoin administration, respectively. Cardiovascular parameters and MCA blood flow were not affected by phenytoin administration. CONCLUSIONS: Phenytoin and fosphenytoin administration at the currently recommended doses achieve plasma unbound phenytoin concentrations within the therapeutic range with few cardiovascular effects. Administration of fosphenytoin i.v. or i.m. offers a practical and convenient alternative to i.v. phenytoin. However, the inadequate control of status epilepticus despite rapid achievement of therapeutic unbound phenytoin concentrations warrants further investigation.     

Concomitant use of mirtazapine and phenytoin: a drug-drug interaction study in healthy male subjects

OBJECTIVE: The objectives of this study were to assess the effect of mirtazapine on steady-state pharmacokinetics of phenytoin and vice versa and to assess tolerability and safety of the combined use of mirtazapine and phenytoin. METHODS: This was an open-label, randomised, parallel-groups, single-centre, multiple-dose pharmacokinetic study. Seventeen healthy, male subjects completed either treatment A [nine subjects: daily 200 mg phenytoin for 17 days plus mirtazapine (15 mg for 2 days continuing with 30 mg for 5 days) from day 11 to day 17] or treatment B [eight subjects: mirtazapine, daily 15 mg for 2 days continuing with 30 mg for 15 days plus phenytoin 200 mg from day 8 to day 17]. Serial blood samples were taken for kinetic profiling on the 10th and 17th days of treatment A and on the 7th and 17th days of treatment B. Induction of CYP 3A by phenytoin was evaluated by measuring the ratio of 6 beta-hydroxycortisol over cortisol on the 1st, 7th and 17th days of treatment B. RESULTS: Co-administration of mirtazapine had no effect on the steady-state pharmacokinetics of phenytoin, i.e. the area under the plasma concentration-time curve (AUC)(0-24) and peak plasma concentration (C(max)) remained unchanged. The addition of phenytoin to an existing daily administration of mirtazapine resulted in a mean (+/-SD) decrease of the AUC(0-24) from 576+/-104 ng h/ml to 305+/-81.6 ng h/ml and a mean decrease of C(max) from 69.7+/-17.5 ng/ml to 46.9+/-10.9 ng/ml. Induction of CYP 3A by phenytoin is confirmed by the significantly ( P=0.001) increased 6beta-hydroxycortisol/cortisol ratio from 1.74+/-1.00 to 2.74+/-1.64. CONCLUSION: Co-administration of mirtazapine did not alter the steady-state pharmacokinetics of phenytoin. The addition of phenytoin to an existing daily administration of mirtazapine results in a decrease of the plasma concentrations of mirtazapine by 46% on average, most likely due to induction of CYP 3A3/4.     

Bioavailability and mammary excretion of bisphenol a in Sprague-Dawley rats.

This study reports the absolute oral bioavailability and mammary excretion of bisphenol A in rats. The oral bioavailability was determined after administration of relatively low iv (0.1 mg/kg) and oral (10 mg/kg) doses of bisphenol A to rats. After iv injection, serum levels of bisphenol A declined biexponentially, with the mean initial distribution and terminal elimination half-lives being 6.1 +/- 1.3 min and 52.5 +/- 2.4 min, respectively. The systemic clearance (Cls) and the steady-state volume of distribution (Vss) averaged 107.9 +/- 28.7 m/min/kg and 5.6 +/- 2.4 L/kg, respectively. Upon oral administration, the maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 14.7 +/- 10.9 ng/ml and 0.2 +/- 0.2 h, respectively. The apparent terminal elimination half-life of bisphenol A (21.3 +/- 7.4 h) after oral administration was significantly longer than that after iv injection, indicating the flip-flop of the absorption and elimination rates. The absolute oral bioavailability of bisphenol A was low (5.3 +/- 2.1%). To determine the extent of mammary excretion, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state at low, medium, and high doses. The steady-state serum levels of bisphenol A were linearly increased with higher dosing rates. The systemic clearance (mean range, 119.2-154.1 ml/min/kg) remained unaltered over the dosing rate studied. The levels of bisphenol A in milk exceeded those in serum, with the steady-state milk to serum concentration ratio being 2.4-2.7.     

Atovaquone has no effect on the pharmacokinetics of phenytoin in healthy male volunteers

The potential pharmacokinetic interaction between atovaquone and phenytoin was investigated in 12 healthy male volunteers. Each volunteer received a single 600  mg oral dose of phenytoin in the two treatment periods. On one occasion phenytoin was taken alone and on the other after pre-treatment with 2000  mg atovaquone taken as two doses of 1000  mg as a microfluidized suspension. The mean (±s.d.) peak plasma concentrations ( C _max), apparent total clearance (CL/ F ) and terminal half-life ( t _½) for phenytoin when administered alone were 10.6(1.8)  mg l⁻¹, 24.3 (7.7)  ml min⁻¹ and 25(8)  h, respectively. When administered together with atovaquone, phenytoin C _max, CL/ F and t _½,z were 10.9 (2.0)  mg l⁻¹, 23.8  ml min⁻¹ and 24(6)  h, respectively. There were no statistically significant differences in any of these plasma pharmacokinetic parameters. There were also no statistically significant differences in the fraction of circulating drug not bound to plasma protein or urinary excretion of 5-hydroxyphenyl-phenyl-hydantoin. In conclusion, there was no effect of atovaquone on the pharmacokinetics of phenytoin or its major metabolite after a single dose.     

Factors influencing simultaneous concentrations of total and free carbamazepine and carbamazepine-10, 11-epoxide in serum of children with epilepsy

Various factors that may influence the simultaneous concentration of total and free carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) in serum of 68 children (mean age 11.8 +/- 4.5 years) with epilepsy were assessed. Separation of free and bound drug fractions was achieved by ultrafiltration, and CBZ and CBZ-E concentrations were determined using a sensitive high pressure liquid chromatographic technique. Thirty children were on CBZ monotherapy. Both total CBZ and CBZ-E serum concentrations correlated significantly with their respective free serum concentrations. CBZ was 81 +/- 3% and CBZ-E 63 +/- 9% bound. There was no correlation between the CBZ dose and either CBZ total or free serum concentrations. A statistically significant correlation was, however, observed between CBZ dose and simultaneous CBZ-E total and free concentrations. CBZ total and free concentrations correlated significantly with those of total CBZ-E. A significant negative correlation was observed between age and total (r = -0.49, p less than 0.01) and free (r = -0.43, p less than 0.025) CBZ-E/CBZ ratios. Concomitant drug therapy (phenytoin, phenobarbitone, and sodium valproate) significantly elevated CBZ-E/CBZ ratios.     

Pharmacokinetics of phenytoin following intravenous and intramuscular administration of fosphenytoin and phenytoin sodium in the rabbit.

The purpose of this study was to evaluate and compare plasma phenytoin concentration versus time profiles following intravenous (i.v.) and intramuscular (i.m.) administration of fosphenytoin sodium with those obtained following administration of standard phenytoin sodium injection in the rabbit. Twenty-four adult New Zealand White rabbits (2.1 +/- 0.4 kg) were anaesthetized with sodium pentobarbitone (30 mg/kg) followed by i.v. or i.m. administration of a single 10 mg/kg phenytoin sodium or fosphenytoin sodium equivalents. Blood samples (1.5 ml) were obtained from a femoral artery cannula predose and at 1, 3, 5, 7, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 min after drug administration. Plasma was separated by centrifugation (1000 g; 5 min) and fosphenytoin, total and free plasma phenytoin concentrations were measured using high performance liquid chromatography (HPLC). Following i.v. administration of fosphenytoin sodium plasma phenytoin concentrations were similar to those obtained following i.v. administration of an equivalent dose of phenytoin sodium. Mean peak plasma phenytoin concentrations (Cmax) was 158% higher (P = 0.0277) following i.m. administration of fosphenytoin sodium compared to i.m. administration of phenytoin sodium. The mean area under the plasma total and free phenytoin concentration-time curve from time zero to 120 min (AUC(0-120)) following i.m. administration was also significantly higher (P = 0.0277) in fosphenytoin treated rabbits compared to the phenytoin group. However, there was no significant difference in AUC(0-180) between fosphenytoin and phenytoin-treated rabbits following i.v. administration. There was also no significant difference in the mean times to achieve peak plasma phenytoin concentrations (Tmax) between fosphenytoin and phenytoin-treated rabbits following i.m. administration. Mean plasma albumin concentrations were comparable in both groups of animals. Fosphenytoin was rapidly converted to phenytoin both after i.v. and i.m. administration, with plasma fosphenytoin concentrations declining rapidly to undetectable levels within 10 min following administration via either route. These results confirm the rapid and complete hydrolysis of fosphenytoin to phenytoin in vivo, and the potential of the i.m. route for administration of fosphenytoin delivering phenytoin in clinical settings where i.v. administration may not be feasible.     

乙醇对苯妥英钠药代动力学的影响

目的 :观察乙醇对苯妥英钠药代动力学的影响。方法 :分别对8只家兔单用苯妥英钠和乙醇合用后苯妥英钠的药代动力学参数变化进行研究和比较 ,采用紫外分光光度法测定苯妥英钠的经 -时血药浓度 ,以“3p87”程序拟合药代动力学参数。结果 :合用乙醇后 ,苯妥英钠的AUC由 (4108 64±1039 98)ml/(L·min)降至 (1903 65±1003 40)mg/(L·min) ;T1/2(ke)由 (98 45±26 4)min降至 (82 84±25 5)min ;Vd 由 (0 3475±0 0360)L/kg升至 (0 6819±0 1901)L/kg ;CLs 由 (0 0026±0 0008)ml/(kg·min)升至(0 0062±0 0022)ml/(kg·min) ;Cmax 由 (29 0±2 94)mg/L降至 (16 0±5 9)mg/L。结论 :合用乙醇后 ,苯妥英钠的消除在体内明显加快     

Oral administration of branched chain amino acids improves virus-induced glucose intolerance in mice

We investigated the therapeutic effect of branched chain amino acids (BCAA) on mice with glucose intolerance induced by encephalomyocarditis virus (EMCV). Male DBA/2 mice were divided into three groups: treated with BCAA, (such as valine, leucine, and isoleucine), untreated, and control. BCAA-treated and -untreated groups were inoculated intraperitoneally with the NDK25 variant of EMCV at 200 plaque-forming units per mouse. The BCAA-treated group was administered orally 0.9 g/kg/day of each BCAA from the day after viral inoculation. The control group neither received virus inoculation nor was treated with BCAA. One week after inoculation, oral glucose tolerance tests (OGTT) were performed. After the glucose loading at 1.5 g/kg of body weight, blood glucose levels in the untreated group were 92.0+/-10.0 mg/dl at baseline, 224.6+/-10.9 mg/dl at 30 min, and 169.4+/-21.4 mg/dl at 60 min, which were significantly (P<0.05) higher than those in the control group (62. 7+/-3.6 mg/dl, 167.2+/-16.4, and 83.8+/-6.0 mg/dl, respectively). Blood glucose levels in the BCAA-treated group were 54.5+/-3.7 mg/dl at baseline, 145.2+/-8.7 mg/dl at 30 min, and 128.7+/-18.3 mg/dl at 60 min after the glucose loading, which were not significantly higher than those in the control group. Immunoreactive insulin levels at 30 min after the glucose loading were lower in the untreated group than in the control group at 1 week after virus inoculation. Histological investigations showed that the grade of insulitis in the pancreas of mice of the BCAA-treated group was lower than that of the mice of the untreated group. These results suggest that oral administration of BCAA is able to improve glucose intolerance induced by EMCV.