Effect of vigabatrin and gabapentin on phynytoin pharmacokinetics in the dog.

The study was aimed at investigating whether or not the kinetics of intravenously administered phenytoin (PT) was altered by oral administration of vigabatrin (VGB) or gabapentin (GBP). A group of five beagle dogs were given a daily dose of PT (12 mg/kg, i.v.) for a period of 1 week. On day 8, plasma samples were serially collected over 24 hr. after administration of the PT dose. PT administration was continued with oral supplementary dose of VGB (60 mg/kg) for another week and then plasma samples were collected for analysis of PT levels. The same protocol was followed for the PT (12 mg/kg, i.v.)-GBP (300 mg caps., p.o.) study on a separate group (n = 5) of dogs. Orally administered GBP did not significantly alter the pharmacokinetic parameters of parental PT. VGB, however markedly changed the drug's kinetics as evidenced by a 31% (P = 0.015) reduction in total body clearance (CL) and increase of over 45% in half-life (t1/2), (P = 0.013) and area under the plasma PT concentration-time curve (AUC), (P = 0.044). GBP does not appear to have any pharmacokinetic interaction with PT, while coadministration of VGB and PT results in marked reduction in systemic clearance of the latter in the dog.     

环丙沙星对苯妥英钠药动学的影响

目的研究环丙沙星对苯妥英血药浓度及药动学参数的影响.方法应用紫外分光光度法测定家兔喂服环丙沙星(25 mg·kg-1)前及1周后单剂量静注苯妥英钠(10 mg·kg-1)的经时血药浓度,以"3P87"药动学程序拟合药动学参数.结果合用环丙沙星后,苯妥英血药浓度明显下降(P<0.05), AUC由合并用药前(6639.0±893.9) mg·L-1·min-1降为(4200.7±874.4) mg·L-1·     

Effect of mushroom diet on pharmacokinetics of gabapentin in healthy Chinese subjects

Aims

This study evaluated the pharmacokinetics of gabapentin in Chinese subjects who received a diet rich in shiitake mushrooms. Shiitake mushrooms have been shown to contain high amount of ergothioneine. In vitro studies have shown that OCTN1-mediated secretion of gabapentin is trans-stimulated by ergothioneine. This study also investigated the concentrations of ergothioneine in plasma at baseline and following mushroom consumption.

Methods

Ten healthy male subjects were recruited and received a diet containing no mushrooms (treatment A) or a high mushroom diet (treatment B; after at least a 7 day washout period) 1 day prior to administration of a single oral dose of gabapentin 600 mg.

Results

Ingestion of shiitake mushrooms produced significant increases in plasma ergothioneine concentrations that were sustained for more than 48 h. A statistically significant but modest increase in the renal clearance (CL_R) of gabapentin occurred after intake of the mushroom diet (91.1 ± 25.1 vs. 76.9 ± 20.6 ml min⁻¹, P = 0.031). No significant changes in AUC(0,t_last) of gabapentin were observed (P = 0.726). Creatinine clearance did not correlate with CL_R of gabapentin at baseline (treatment A). After ingestion of the mushroom diet, creatinine clearance accounted for 65.3% of the variance in CL_R of gabapentin.

Conclusions

These data suggest that diet–drug pharmacokinetic interactions may occur during co-exposure to gabapentin and mushroom constituents. However, as it does not affect the AUC(0,t_last) of gabapentin, it may not have clinically important consequences. Shiitake mushrooms can also be used as a source of ergothioneine for future clinical studies.     

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     

LC-MS/MS法测定人血浆中加巴喷丁的浓度及其药动学研究

建立液相色谱串联质谱(LC-MS/MS)法测定人血浆中加巴喷丁的浓度并将其应用于人体药动学研究。取血浆样品经甲醇沉淀蛋白后,以甲醇0.2%甲酸水溶液(80∶20)为流动相,用Inertsil ODS-3 C18柱(50 mm×2.1 mm ID,3μm)分离,采用电喷雾离子源,以多反应监测(MRM)方式进行正离子检测,定量分析的离子反应分别为m/z 172→m/z 154(加巴喷丁)和m/z 130→m/z 71(内标二甲双胍)。加巴喷丁线性范围为40.8～8.16×103 ng.mL 1,定量限为40.8 ng.mL 1,每个样品测试时间仅2.2 min,日内、日间精密度(RSD)均小于12%,准确度(RE)在±6.4%范围内。应用此法研究了20名健康志愿者单剂量口服加巴喷丁胶囊600 mg后的药动学特点。该方法快速、专属、灵敏、适用性强,可应用于加巴喷丁的人体药动学研究。     

Bioavailability and pharmacokinetics of phenytoin during pregnancy

Summary Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration — time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in nonpregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.     

The clinical pharmacokinetics of phenytoin

Procedures for estimating the variability in dosage requirements of phenytoin to achieve steadystate plasma concentrations of 10–20 mg/liter and for estimating the plasma concentrations produced on a fixed dose are given. Further, a method is proposed for estimating the dosage required to achieve a desired steady-state plasma phenytoin concentration when a steady-state value on a known daily dose has been measured, A method is also described for estimating dosage requirements when two or more plasma concentrations have been measured. These methods are derived from data obtained on administering phenytoin in four to five different dosage regimens until steady state was achieved in each of nine volunteers. The drug was administered orally as a suspension every 8 hr, starting with about 100mg/day. The daily dose was increased in steps, and maintained at each daily dose rate for 6–14 days, or longer. Blood samples were drawn 4 and 8 hr after the last dose on 2 successive days at the end of each step and analyzed for phenytoin concentration. The average of these values was used to estimate the steady-state plasma concentration, C_pss. For each subject the C_pss values were fitted to a rearranged Michaelis-Menten equation C_pss =K_mR/(V_m-R). In this equation R is the dosing rate, V_m is the maximum rate of metabolism, and K_m is a constant equal to the plasma concentration at which the metabolism rate is one-half maximum. The average values found for V_m and K_m were 10.3 mg/kg/day and 11.54 mg/liter, respectively. The individual values of V_m and K_m appear to be constant over time, but there is considerable interindividual variability: coefficients of variation are 25% and 50%, respectively.Supported in part by grants (GM-16496, GM-01791, and GM-00001) from the National Institutes of Health. Dr. Martin was a recipient of a grant from the Swiss National Research Foundation.     

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.     

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]     

普萘洛尔对精神分裂症患者体内氯氮平药动学的影响研究

目的：研究精神分裂症患者体内普萘洛尔对氯氮平血药浓度及药动学的影响。方法：选取24位精神分裂症患者,进行氯氮平片试验制剂和参比制剂的随机、开放、2周期交叉的空腹生物等效性试验,其中15人早晚服用氯氮平片100 mg,另外9人服用氯氮平片+普萘洛尔,每周期在固定的时间点进行血样采集,应用高效液相色谱-串联质谱法检测血样中氯氮平的浓度,使用WinNonlin 7.0软件计算参比制剂组氯氮平的药动学参数。结果：与单用氯氮平相比,合并使用普萘洛尔后,氯氮平的平均AUC_0-12、C_min,ss及C_av,ss均显著增高（P=0.043,P=0.017和P=0.042）;合用普萘洛尔组的氯氮平C_max,ss均值也较单用氯氮平组高[（854.11±286.47） ng·mL^-1 vs.（671.14±160.98） ng·mL^-1],但差异无统计学意义;合用普萘洛尔组氯氮平的平均t_1/2显著长于单用氯氮平组（P=0.001）。结论：合并使用普萘洛尔可显著增加氯氮平的系统暴露量,在临床上需注意普萘洛尔对氯氮平的影响。     

Effect of cholestyramine and colestipol on the absorption of phenytoin

Summary The hypocholesterolemic cation resins, cholestyramine and colestipol, have variable effects on the absorption parameters of a number of lipophillic, anion drugs. Because of the unpredictable nature of this interaction, we have assessed in human volunteers the effect of these resins on the rate and total absorption of phenytoin. Our results indicate that these resins do not affect the absorption parameters of phenytoin and that special care does not have to be exercised when these agents are co-administered.     

Effect of short-term administration of garlic supplements on single-dose ritonavir pharmacokinetics in healthy volunteers

AIMS: To evaluate the effect of acute dosing of garlic supplements on the single-dose pharmacokinetics of ritonavir. METHODS: Ten healthy volunteers (five male, five female) were equally randomized in a crossover design to receive 400 mg of a single dose of ritonavir within 10 min after eating breakfast either alone or with 10 mg of Natural Source Odourless Garlic. They received a total of eight doses of garlic extract (2 x 5 mg capsules) taken twice daily for 4 days. Ritonavir and the seventh garlic dose were administered simultaneously. RESULTS: Coadministration of garlic nonsignificantly decreased area under the plasma concentration-time curve (AUC(0, infinity )) by -17% (90% confidence interval (CI), -31% to 0%; range -46% to 68%) and peak plasma concentration of ritonavir by -1% (90% CI, -25% to 31%; range -51% to 136%). CONCLUSIONS: Acute dosing of the garlic capsules over 4 days did not significantly alter the single-dose pharmacokinetics of ritonavir in healthy volunteers. Given the complex effects of both ritonavir and garlic on drug metabolism, the results of our study should not be extrapolated to steady-state conditions, where the possibility of an interaction still needs to be evaluated.     

苯妥英钠对大鼠伤口巨噬细胞的影响

本实验旨在研究苯妥英钠(PS)对伤口巨噬细胞(M_ф)的影响. 从置入大鼠背部伤口的聚乙烯醇海绵中收集巨噬细胞, 分别测定其吞噬功能, 肿瘤坏死因子α(TNF_α)和白介素1(IL-1)的释放以及对成纤维细胞增殖调节作用, 通过牵拉伤口组织致其断裂时溢出的水的重量而测定伤口牵张强度. 结果表明, 伤口M_ф的功能在伤后d 5达到高峰, PS 1,10,50 g·L^-1浓度依赖性地增加伤后d 5的伤口M_ф的数量, 吞噬功能, TNF_α和IL-1的释放, 增强M_ф对成纤维细胞增殖的刺激作用, 增强伤口牵张强度. 结果说明PS加速伤口愈合, 与其增强M_ф的功能有关.     

原子吸收法测定犬体内顺铂聚乳酸微球的药物动力学

目的:研究犬体内顺铂聚乳酸微球(CDDP-PLA)药物动力学。方法:20只杂种狗随机分为栓塞组和对照组。栓塞组 X线透视下CDDP-PLA经导管注入肝动脉,静脉取血,1 mg·kg^-1微球。对照组 CDDP,1 mg·kg^-1,其他同前。3P97软件处理药-时数据,原子吸收法测定血药浓度。结果:血浆CDDP动力学过程为三室;肝动脉灌注后8 h肝组织CDDP浓度分别为(22.08±12.15)μg·ml^-1(微球组)和(3.25±0.09)μg·ml^-1 (对照组),差异显著(P<0.05)。结论:CDDP-PLA具有良好的肝动脉栓塞性能,使栓塞部位组织CDDP浓度维持较长时间和较高浓度,同时降低体循环浓度,降低CDDP全身毒性。     

Evidence for both in vivo and in vitro interaction between vigabatrin and alanine transaminase

Aims Decreases in plasma alanine transaminase (ALA-T) activity of 20–100% have been reported following the use of vigabatrin (Sabril) in patients with uncontrolled epilepsy. This effect has a potential clinical significance as it may mask signs of early, underlying hepatic disease. It is particularly significant in a patient population known to have a higher than average risk of hepatotoxicity due to treatment with other anti-epilepsy drugs or to an independent, but concomitant, disease process. Vigabatrin is a highly specific enzyme antagonist. There is an almost 1000-fold difference between its activity against γ-amino butyric acid aminotransaminase and ALA-T. However, some activity against other transaminases is not unexpected, and it is important to determine the degree of vigabatrin''s effect against ALA-T in man. Methods Two in vitro experiments, using serum samples spiked with vigabatrin, confirmed the presence of an interaction between vigabatrin and ALA-T, and formed the basis for the design of a study in five healthy male volunteers, in whom serum ALA-T activity was measured before and after a single dose of 1.5 g of vigabatrin. Results Serial sampling confirmed the presence of an in vivo interaction between vigabatrin and ALA-T, causing an inhibition of enzyme activity of 30–40%. A further 20% reduction was found in vitro in samples taken at the time of the peak plasma vigabatrin concentration after they had been stored for 6 h. Conclusions The clinical significance of these findings is that the levels of ALA-T activity determined in patients receiving vigabatrin may be inaccurate. The ‘real’ values must be assumed to be higher than those reported after routine testing. To obtain the most realistic measurement of ALA-T activity in patients, samples should be taken at the times of trough plasma concentration and processed as soon as possible afterwards. Samples stored for any length of time at or above room temperature may also give even more false results.     

The effect of vigabatrin on cognitive function and mood

Cognitive function and mood have been assessed in nine patients started on vigabatrin as additional therapy to their regular anticonvulsants. Psychological tests were given at baseline (S1) and at 4 weeks (S2) after starting treatment. A comparison group of nine patients on stable therapy was tested at the same time intervals. In particular, tasks with minimal or no motor components were used. Mood was rated with the Beck Depression Inventory. The vigabatrin group scored significantly higher on a task of attention and concentration at S2. This was not related to change of seizure frequency or serum levels of other anticonvulsants. No effects were observed on mood.     

Effect of phenytoin sodium on macrophages in rat wounds

本实验旨在研究苯妥英钠（ＰＳ）对伤口巨噬细胞（Ｍ）的影响．从置入大鼠背部伤口的聚乙烯醇海绵中收集巨噬细胞，分别测定其吞噬功能，肿瘤坏死因子α（ＴＮＦα）和白介素１（ＩＬ－１）的释放以及对成纤维细胞增殖调节作用，通过牵拉伤口组织致其断裂时溢出的水的重量而测定伤口牵张强度．结果表明，伤口Ｍ的功能在伤后ｄ５达到高峰，ＰＳ１，１０，５０ｇ·Ｌ－１浓度依赖性地增加伤后ｄ５的伤口Ｍ的数量，吞噬功能，ＴＮＦα和ＩＬ－１的释放，增强Ｍ对成纤维细胞增殖的刺激作用，增强伤口牵张强度．结果说明ＰＳ加速伤口愈合，与其增强Ｍ的功能有关．     

Gastrointestinal absorption of phenytoin from an oil-in-water microemulsion

The absorption profile of phenytoin Na emulsion were examined compared to that of phenytoin suspension after oral administration in the rat. The corn oil-in-water emulsion, particle size of 184±57.8 nm, was prepared using a microfludizer, and phenytoin Na added by shaft homogenizer. The phenytoin emulsion or suspension, 100 mg/kg, were intubated intragastrically using oral dosing needle and blood samples were withdrawn via an indwelling cannula from the conscious rat. Plasma concentrations of phenytoin were measured with HPLC using phenacetin as an internal standard. The plasma concentration versus time data were fitted to a one compartment open model and the pharmacokinetic parameters were calculated using the computer program, Boomer. The phenytoin plasma concentrations from the emulsion at each observed time were about 1.5–2 times higher than those from the suspension, significantly at time of 5, 6 and 7 hr after administration. The absorption (k_a) and elimination rate constant (k_e) were not altered significantly, however the AUC increased from 65.6 to 106.7 μg·hr/ml after phenytoin suspension or emulsion oral administration, respectively. From an equilibrium dialysis study, the diffusion rate constant (k_IE) was considerably higher from the phenytoin Na emulsion (0.0439 hr⁻¹) than phenytoin suspension (0.0014 hr⁻¹).     

A comparative study of the pharmacokinetics of traditional and automated dosing/blood sampling systems using gabapentin

Objective:

The present study was undertaken to investigate the pharmacokinetics (PKs) of gabapentin as determined by traditional manual blood sampling and by using an automated dosing/blood sampling technique in awake and freely moving rats using combined liquid chromatography tandem mass-spectrometry (LC-MS/MS).

Materials and Methods:

PK comparisons were conducted by allocating rats into two groups; an automated dosing/blood sampling (ADI/ABS) group (IV study, n = 6 and intragastric study, n = 6) and a manual group (IV study, n = 6 and oral study, n = 6). A series of blood samples from carotid artery were taken at specified times and analyzed using a validated LC-MS/MS method. Various PK parameters like area under curve (AUC_inf), maximum concentration, time to reach maximum concentration, terminal half life, distribution volume at the steady state, and total clearance were calculated and the two study groups were compared with respect to these parameters.

Results:

Significant differences in PK parameters were observed between the manual group and the ADI/ABS group and respective bioavailability were measured (46.82 ± 19.45% and 61.54 ± 21.23%, respectively) which is 1.31-fold difference (P = 0.0051, P<0.05).

Conclusion:

The described ADI/ABS method was found to be a useful drug development tool for accelerating the pace of preclinical in vivo studies and for obtaining reliable and accurate PK parameters even from single animals as it minimized interanimal and physiological variations.