Effect of Tamoxifen on the Pharmacokinetics of Theophylline in Rats

The effect of tamoxifen on the pharmacokinetics of theophylline was investigated in male Sprague–Dawley rats. The oral administration of tamoxifen at a dose equal to 40 mg kg^?1 48 h before the intravenous injection of theophylline 10 mg kg^?1, significantly (P < 005) increased the clearance of theophylline by 39%, with no apparent effect on the volume of distribution. As a consequence, the elimination half-life of theophylline was significantly (P < 005) shortened in the tamoxifen-treated rats (3.56 ± 0.39 h vs 5.25 ± 0.48 h) as well as its mean residence time (5.04 ± 0.60 h vs 7.50 ± 0.75 h). Although these data cannot be directly extrapolated to the clinical situation, they provide experimental support to suggest that more attention should be paid to the potential risk of pharmacokinetic interactions in the presence of tamoxifen.     

Effects of Baicalin on Oral Pharmacokinetics of Caffeine in Rats

Scutellaria baicalensis is one of the most widely used herbal medicines in East Asia. Because baicalein and baicalin are major components of this herb, it is important to understand the effects of these compounds on drug metabolizing enzymes, such as cytochrome P450 (CYP), for evaluating herb-drug interaction. The effects of baicalin and baicalein on activities of ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), benzyloxyresorufin O-debenzylase (BROD), p-nitrophenol hydroxylase and erythromycin N-demethylase were assessed in rat liver microsomes in the present study. In addition, the pharmacokinetics of caffeine and its three metabolites (i.e., paraxanthine, theobromine and theophylline) in baicalin-treated rats were compared with untreated control. As results, EROD, MROD and BROD activities were inhibited by both baicalin and baicalein. However, there were no significant differences in the pharmacokinetic parameters of oral caffeine and its three metabolites between control and baicalin-treated rats. When the plasma concentration of baicalin was determined, the maximum concentration of baicalin was below the estimated IC₅₀ values observed in vitro. In conclusion, baicalin had no effects on the pharmacokinetics of caffeine and its metabolites in vivo, following single oral administration in rats.     

Pharmacokinetics of Pentoxifylline During Concomitant Theophylline Administration to Rats

Pharmaceutical Research -     

Effects of Capsaicin on the Pharmacokinetics of Antipyrine,Theophylline and Quinine in Rats

Abstract— Capsaicin is the active principal of capsicum fruits, such as hot peppers. The influence of 1-week pretreatment of capsaicin (25 mg kg^?1) on the pharmacokinetics of antipyrine, theophylline and quinine was investigated in rats. The drugs were given as an intravenous bolus dose. The control rats received the vehicle solvent (polyethylene glycol) only. Clearance of antipyrine in the capsaicin-pretreated rats was significantly lower than that observed in the control rats (0·241 ± 0·029 vs 0·344 ± 0·034 L h^?1 kg^?1, P < 0·05). This is consistent with a prolongation in the elimination half-life of antipyrine in animals pretreated with capsaicin (2·06 ± 0·30 vs 1·61 ± 0·27 h), as the volume of distribution was not significantly changed. In contrast, capsaicin pretreatment had no significant effect on the pharmacokinetics of theophylline and quinine.     

头孢哌酮对茶碱药动学的影响

目的：了解头孢哌酮对茶碱药代动力学(药动学)的影响,为临床合理使用茶碱提供数据.方法：健康家兔6只,受试前未使用过任何药物,静脉注射4.00 mg&#8226;mL 1茶碱溶液10 mg&#8226;kg 1,10 min注射完毕.给药后于其耳缘静脉定时取血,采用高效液相色谱法测定家兔体内茶碱浓度：用甲醇提取血清样品中的茶碱,色谱柱为Shim pack ODS C18；流动相为甲醇：水(70∶30),流速为0.8 mL&#8226;min 1；检测波长为252 nm；柱温为30℃；进样量10 μL.求算药动学参数.结果：头孢哌酮使茶碱的曲线下面积(AUC),半衰期(T1/2)和表观分布容积(Vd)下降；消除速率常数(Ke)升高；清除率(CL)无明显变化.结论：头孢哌酮对茶碱药代动力学参数有影响,临床合用时应注意调整茶碱的用量.     

慢性阻塞性肺病者人茶碱药物动力学研究

本实验用萤光偏振免疫分析仪(TDX)测定茶碱血药浓度。对8名老年慢性阻塞性肺病(COPD)患者进行了氨茶碱口服多剂量给药的药物动力学研究。血药浓度数据在IBM—PC计算机上用PKBP-Ni程序处理,得到老年COPD患者的茶碱药物动力学参数,房室模型以一拟合。消除速率常数(Ke)为0.0555±0.0111h~(-1),消除半衰期(T1/2)为13.01±2.98h,表观分布容积(Vd)为29.42±6.80L,清除率(CL)为1.61±0.37L/h,曲线下面积(AUC)为131.3±33.8hmg/L。本实验得到的COPD老人茶碱的T1/2比文献报道的健康老人的T1/2有明显延长,CL有所下降。     

莫昔沙星对家兔茶碱药动学的影响

目的：探讨莫昔沙星对茶碱药动学的影响，为临床合理用药提供参考。方法：采用自身对照法，给家兔静脉注射茶碱10 mg·kg 1后测定血浆中茶碱浓度，停药7 d后，灌胃给予莫昔沙星20 mg·kg 1，qd，连续6 d，再静脉注射茶碱10 mg·kg 1后测定血浆中茶碱浓度，计算药动学参数。结果：合用莫昔沙星前后茶碱呈一室模型，K值分别为(0.162±0.057)，(0.158±0.059 )h 1；t1/2分别为(4.79±1.85)，(5.16±2.26) h；V分别为(0.524±0.109)，(0.516±0.114) L·kg 1；AUC0～10分别为(97.39±12.40)，(101.27±16.49) mg·h 1·L 1；CL分别为(0.081±0.018)，(0.077±0.021) L·kg 1·h 1；Cmax分别为(20.09±3.77)，(20.53±4.21) mg·L 1，合用莫昔沙星前后茶碱的药动学参数差异无显著性(P＞0.05)。结论：莫昔沙星对茶碱的血药浓度及药动学参数没有明显影响。     

非洛地平对兔体内茶碱药动学的影响

目的:观察新西兰白兔灌服非洛地平前后茶碱血药浓度及药动学参数的改变.方法:实验分为两期,Ⅰ期:6只兔单独灌服氨茶碱,连续给药4 d后定时采血;Ⅱ期:合用非洛地平与氨茶碱7 d,每次给药量氨茶碱30 mg&#8226;kg 1,非洛地平1 mg&#8226;kg 1.采用荧光偏振免疫分析法测定茶碱血药浓度.对两期药动学参数进行统计分析.结果:与Ⅰ期比较,Ⅱ期的消除半衰期(t1/2β)、消除速率常数(Ke)、表观分布容积(V&#8226;C/F)差异有极显著性或差异有显著性(P＜0.01,P＜0.05),AUC、Cmax、tmax、Ka、t1/2α均差异无显著性(P＞0.05).结论:长期合用非洛地平和氨茶碱,非洛地平能延缓茶碱在兔体内的消除,但需要密切监测茶碱的血药浓度     

Evaluation of Transdermal Theophylline Pharmacokinetics in Neonates

Theophylline may be administered by several routes, but problems are associated with neonatal dosing. The transdermal route may provide a safer and noninvasive method of administration, yet produce therapeutic concentrations in a consistent and reliable manner. To study the feasibility of this in the apnea of prematurity, stable neonates were administered a subtherapeutic transdermal dose for 24 hours in order to assess pharmacokinetics and bioavailability. This was followed with routine intravenous theophylline therapy according to institutional policy. Six of nine neonates had detectable serum theophylline concentrations that increased slowly after patch application. Mean (± SD) maximum serum concentration was 2.4 ± 1.3 μg/ml, mean time to maximum serum concentration was 22 ± 8.2 hours, and mean latency period was 8.0 ± 4.9 hours. Mean total amount of theophylline delivered to the skin was 18.6 ± 4.1 mg. Mean fractional absorption at 30 hours was 0.25 ± 0.12. These data demonstrate that it is possible to produce systemic theophylline concentrations with a transdermal patch in preterm infants sufficient to study pharmacokinetics and bioavailability, and that transdermal delivery of therapeutic doses is technologically feasible.     

HPLC法测定复方茶碱麻黄碱片中可可碱、盐酸麻黄碱、茶碱和咖啡因的含量

建立HPLC法测定复方茶碱麻黄碱片中可可碱、盐酸麻黄碱、茶碱和咖啡因的含量。采用D iamonsil C18色谱柱,以0.05mol.L-1磷酸二氢钾-甲醇-三乙胺(77∶23∶0.2)为流动相,检测波长为215nm。线性范围为可可碱:0.1011~0.9097μg(r=0.9998);盐酸麻黄碱:0.0418~0.3758μg(r=0.9999);茶碱:0.0973~0.8759μg(r=0.9999);咖啡因:0.0614~0.5522μg(r=0.9999),平均回收率为可可碱:99.8%(RSD=0.6%,n=9);盐酸麻黄碱:100.4%(RSD=0.9%,n=9);茶碱:99.6%(RSD=0.5%,n=9);咖啡因100.1%(RSD=0.3%,n=9)。本方法简便、快速,专属性强,可有效地控制复方茶碱麻黄碱片中可可碱、茶碱、咖啡因和麻黄碱的含量。     

咖啡因,可可碱和茶碱的电喷雾质谱

目的：应用电喷雾质谱法对嘌呤生物碱咖啡因、可可碱和茶碱进行了质谱研究。方法：改变ＣＯＮＥ电压。结果：ＣＯＮＥ电压较低时,３个生物碱不发生裂解,其各自的［Ｍ＋Ｈ］＋峰为基峰,可获得分子量信息。ＣＯＮＥ电压升高后,３个生物碱均发生主要裂解,其中咖啡因和茶碱较可可碱易发生裂解。结论：结果表明这些裂解方式可用于结构分析。     

Pharmacokinetics and Dose Regimen of Oral Theophylline in Children

Abstract: The pharmacokinetics of theophylline after oral administration in tablet (Oxyphyllin®) or solution (Teovent®) form was determined in 22 children 0.6–16 years of age. Four of these children also received intravenous theophylline. The absorption of theophylline both from the tablets and from the solution was rapid (mean half-time 14.3 and 16.1 min., respectively) and almost complete. The youngest children (2–8 years) given tablets had a significantly shorter half-time of elimination and a higher total plasma clearance than children aged 9–16 years. Adverse effects during treatment with the oral solution were studied in another 19 children. Medication was stopped by the parents of two children because of the unpleasant taste. Gastrointestinal disturbances were frequent but not serious enough to cause discontinuation of treatment. Simulations based on obtained pharmacokinetic data showed that in the average child below nine years of age oral theophylline, 6–8 mg/kg three times daily, would give plasma levels between 10 and 20 μg/ml (55–110 μmol/l) for about 60–70% of the day. A dose of 6 mg/kg four times daily would achieve such concentrations during almost 24 hrs of the day. In the average child aged 9–16 years a reduced dose of about 5–6 mg/kg three times daily would suffice to produce plasma levels of 10–20 μg/ml owing to the slower elimination of the drug in this age group. Individual titration of the dose is necessary for optimal treatment with theophylline in all age groups.     

双黄连对氨茶碱药动学的影响

目的 :研究双黄连对氨茶碱在人体内药动学的影响。方法 :采用高效液相色谱法测定8名健康志愿者多剂量服用双黄连口服液前、后氨茶碱的血药浓度 ,以3p97药动学软件按一室模型对数据进行处理 ,并对结果进行统计学分析。结果 :单用氨茶碱和合用双黄连后氨茶碱的Tmax 分别为 (1 66±0 56)、(1 59±0 78)h ,Cmax 分别为 (6 23±1 31)、(6 10±0 94) μg/ml ,T1/2 分别为(5 76±1 11)、(6 09±1 63)h ,CL分别为 (47 72±5 12)、(50 98±10 85)ml/(kg·h) ,Vd分别为 (369 18±40 15)、(430 37±48 33)ml/kg,AUC0→∞分别为 (84 56±14 43)、(89 27±26 35) μg/(h·ml)。结论 :双黄连明显增加氨茶碱的Vd ,对Tmax、Cmax、T1/2、CL和AUC0→∞没有影响     

Bioavailability and Pharmacokinetics in Man of Orally Administered Theophylline

Abstract The pharmacokinetics of theophylline after both intravenous and oral administration was investigated in six hospitalized patients with normal renal, hepatic and pulmonary functions. A rather wide range of biological half-lives from about 3–16 hours and plasma clearance values of about 16.5–115 ml kg^-1 hr^-1 were found in the investigated patients, who were from 31 to 73 years of age. The apparent volumes of distribution during the eliminatory β-phase (V_dβ) were within the range 0.394–0.616 1 kg^-1 with a mean value of 0.484 1 kg^-1 ±0.082 S.D., as determined from the intravenous data, and in excellent agreement with the value obtained from the peroral data. Except in one case theophylline exhibited two compartment characteristics after intravenous administration, while the oral data in only one patient showed this pharmacokinetic configuration and had to be analysed according to one-compartment characteristics in the other five subjects. In the oral experiments absorption rate constants of from about 0.57 to 2.17 hr^-1 were found for the administered microparticulate theohylline tablet preparation, Nuelin® from Riker Laboratories. A wide range of lag-times from 0 to 1.32 hours were also demonstrated in the experiments. The systemic availability of theophylline in this preparation varied from 82.8 to 103% as determined on basis of the ratios of areas under the oral and intravenous serum concentration curves. It is conclusively stated that therapeutic plasma concentrations of theophylline probably may be maintained and controlled efficiently with the investigated oral theophylline preparation. Because of the interindividual variability in the biological half-life of the compound monitoring of the serum theophylline concentration is generally advised in order to avoid toxic side effects, in particular in relation to the initial establishment of a therapeutic serum concentration level in the individual subjects to be treated.     

The Effect of Amiodarone on Theophylline Pharmacokinetics in the Rat

Amiodarone is an investigational antiarrhythmic agent which has been implicated in reducing the activity of the hepatic mixed-function oxidase system. To evaluate this effect further, two groups of six male Sprague–Dawley rats each received theophylline (6 mg/kg, iv) preceded by either normal saline or amiodarone HC1 (100 mg/kg, iv). Blood samples were obtained serially for a period of 6 hr and the sera were assayed for theophylline by high-pressure liquid chromatography (HPLC). In rats pretreated with amiodarone, a significant 45% reduction in the mean (± SD) systemic clearance [0.057 (0.010) vs 0.031 (0.004) liter/hr/kg, P < 0.001] and a greater than 100% increase in the mean elimination half-life [2.03 (0.46) vs 4.29 (0.71) hr, P < 0.001] of theophylline were observed. These data demonstrate an acute inhibitory effect of amiodarone on the hepatic microsomal enzyme system.     

The Effect of Isradipine on Theophylline Pharmacokinetics in Healthy Volunteers

The effects of isradipine 2.5 mg and 5 mg on the disposition of theophylline were investigated in a placebo-controlled, randomized, three-way, crossover trial. Eleven healthy, nonsmoking men each received a treatment of placebo, and isradipine 2.5 mg and 5 mg every 12 hours for 6 consecutive days. On the morning of day 6, 2 hours after the isradipine dose, theophylline (solution) 5.0 mg/kg was administered orally, and blood samples were collected over 24 hours. A 2-week washout period separated treatment sequences. Plasma samples were analyzed for theophylline using high-performance liquid chromatography. Using a two-way analysis of variance, no significant changes in apparent theophylline clearance were observed between placebo, and isradipine 2.5 and 5 mg (0.815 ± 0.164, 0.870 ± 0.212, and 0.827 ± 0.164 ml/min/kg, respectively; p=0.136). Similarly, no significant change in volume of distribution was noted. These findings suggest that isradipine at recommended dosages does not impair theophylline metabolism.     

Influence of Grapefruit Juice on Caffeine Pharmacokinetics and Pharmacodynamics

The influence of grapefruit juice (GFJ) on caffeine's metabolism and the hemodynamic effects of this potential food interaction were studied in 10 normotensive volunteers. In this crossover study, caffeine (3.3 mg/kg) and water or caffeine and GFJ were given to participants. Nine serum caffeine concentrations were determined within 24 hours of each phase. In another phase of this study, caffeine was given with multiple GFJ doses to 6 of the 10 participants. Ambulatory blood pressure (BP) monitors were used for 12 hours to assess treatment hemodynamic effects. The mean area under the serum caffeine concentration-time curve (AUC_0–∞) values ± SD for the caffeine with water group, caffeine with GFJ group, and caffeine with multiple GFJ group were 47.0 ± 10.8, 48.7 ± 15.2, and 49.6 ± 7.0 μg/ml · hr, respectively (NS). There was no significant difference on the ambulatory systolic BP, diastolic BP, percentage of the time with a diastolic BP greater than 90 mm Hg, or heart rate area under the effect curves. We conclude that grapefruit juice had no effect on caffeine pharmacokinetics or hemodynamic effects.     

Reproductive Effects of Theophylline in Mice and Rats

Reproductive Effects of Theophylline in Mice and Rats. MORRISSEY,R. E., COLLINS, J. J., LAMB, J. C, IV, MANUS, A. G., AND GULATI.D. K. (1988). Fundam Appl. Toxtcol. 10, 525–536. Theophyllinewas administered by gavage in 13-week studies to B6C3F, mice(0, 75, 150, 300 mg/kg/day) and F344 rats (0, 37.5, 75, 150mg/kg/day) with significant reductions in male mouse terminalbody and testicular weights. Male rats also displayed reducedtesticular weight, as well as nonsignificant but dose-relateddecreases in body weight. There was a significant but non-dose-relateddecrease in female mouse body weight. In parallel studies ofB6C3F, mice and F344 rats, theophylline administered in thediet (0, 0.1, 0.2, 0.4%) produced significantly decreased terminalbody weights in male and female mice, but not rats. In rats,cauda epididymis weight was reduced at the high dose comparedto the control group, and there was an increase in abnormalsperm. These studies were followed by continuous breeding reproductiveassays in CD-I mice in which theophylline was administered infeed (0.0, 0.075, 0.15, and 0.30% calculated doses of 0, 125,265, and 530 mg/kg/day, respectively) to breeding pairs for14 weeks. There was a dose-dependent decrease in the numberof live pups produced per litter, a significant decrease inthe number of litters produced per pair (0.30%) and in the adjustedlive pup weight (0.30%), a decrease in the percentage of pupsborn alive (0.15 and 0.30%), and an increase in the number ofdays needed to produce each litter (0.30%). After 19 weeks ofcontinuous treatment at 0.307%, a crossover mating trial indicatedthat females and males were adversely affected by theophylline,as judged by the decreased percentage of pups born alive, thedecreased live pup weight, and the decreased number of livepups per litter relative to matings within the control group,but the effects in females were more extensive. Based on otherstudies, there is a suggestion that the observed changes infertility may be partially attributed to embryotoxicity.     

Effect of Stress on the Pharmacokinetics of Sodium Salicylate and Quinidine Sulphate in Rats *

Abstract: Studies on the influence of foot shock stress on the absorption, distribution and overall serum elimination of sodium salicylate and quinidine sulphate were performed in rats. Foot shock stress was produced by grid floor electrical stimulation. The animals were stressed 1 hr before administration of the drugs and then throughout the experimental period. A significant induced stress was demonstrated by increased blood glucose levels and increased whole brain turnover of noradrenaline. Gastric emptying and intestinal transit as well as tissue levels of the drugs in the serum, heart, brain, liver, muscle and fat were determined. Results were obtained indicating that stress produced a significant increase in the gastro-intestinal absorption of quinidine sulphate while no change in the distribution pattern or overall elimination was noted. On the other hand, sodium salicylate did not show any marked change in the pharmacokinetic parameters during a stressful situation.     

On the Pathogenesis of Cardiac Necroses induced by Theophylline and Caffeine

Abstract In unanesthetized rats, theophylline or caffeine in a dose of 150 mg/kg intraperitoneally caused a long–lasting tachycardia, hypermetabolism and hypotension. After 48 hours myocardial necroses were found in all the animals. Propranolol diminished the cardiotoxic as well as the chronotropic, calorigenic and hypotensive effects of theophylline. The calcium antagonists verapamil and D 600 were ineffective in this respect but augmented the acute toxicity of theophylline. Furthermore, the cardiotoxic activity of theophylline was intensified by pretreatment with thyroxine. Total myocardial calcium increased within one hour after the injection of a cardiotoxic dose of isoprenaline (10 mg/kg intraperitoneally) but not after theophylline (150 mg/kg intraperitoneally). Only 24 hours after the theophylline treatment were the myocardial calcium levels elevated. In conclusion, cardiac necroses may be a consequence of hypoxia resulting from the cardiovascular and metabolic actions of theophylline or caffeine. Myocardial calcium overloading does not seem to be an essential factor in the pathogenesis of these necroses.