Comparative bioavailability of a microcrystalline theophylline tablet and uncoated aminophylline tablets

Summary The bioavailability of a rapidly dissolving tablet of theophylline and three brands of standard aminophylline tablets was estimated in a four way cross-over study involving 8 healthy adult volunteers. The relative extent of bioavailability as assessed by the measurement of the total area under the plasma concentration time curves showed no difference between the products (P>0.05). Computed estimates of the rate of drug absorption were similar for all 4 products tested. The results indicate that the rapidly dissolving tablet offers no advantage in respect to rate and extent of absorption over conventional aminophylline tablets.     

Disposition and clinical pharmacokinetics of theophylline after administration of a new sustained release tablet

Summary The systemic disposition of theophylline after taking a new, sustained release tablet (Theolair Retard^® 250 mg, Theolair S. R.^®, Riker Laboratories) has been studied in 8 hospitalized patients. Absolute bioavailability was determined from the ratios of the areas under the serum concentration-time curves after intake of the tablet and after intravenous infusion of aminophylline in the same patient. The absolute bioavailability of Theolair Retard^® 250 mg was 110.9±20.8% (mean ± SD). Maximal serum concentrations were reached after 7.3±3.5 h, the large intersubject variation being due to differences in gastric emptying time. The tablets appear to release theophylline slowly in acid conditions, but more rapidly in an alkaline medium. Invasion was found to be either monophasic with a rate constant of about 0.8 h^–1 (intestine), or biphasic with rate constants of 0.2 h^–1 (stomach) and 0.8 h^–1 (intestine). The peak levels accounted for 7.9±2.2 mg · 1^–1. The profiles of the serum concentration-time curves were such that the concentrations remained above 80% of c^max for 6.5±3.3 h. The relevant pharmacokinetic parameters (half-life of elimination, total body clearance and volume of distribution) were determined and were used to calculate the individual dosage regimens required to obtain therapeutic serum concentrations. The optimal dosing interval to obtain an average steady state serum concentration of 12.5 mg · l^–1 was 9.8±3.1 h.     

Pharmacokinetics of a microcrystalline theophylline preparation in patients with chronic obstructive airways disease

Summary Plasma theophylline concentrations have been measured in 9 patients with chronic obstructive airways disease following the oral administration of a microcrystalline theophylline preparation. Some measurements of FEV₁ were also made. Four patients were given 375 mg as a single dose and then subsequently 375 mg stat and 125 mg 4 times daily for 3 days, (Group I). A further 5 patients took 250 mg as a single dose and then 250 mg 4 times daily for 3 days, (Group II). In both groups, following the single dose and again after the last dose of chronic administration, blood samples were obtained at frequent intervals up to 24 h for plasma drug estimation. During the 3-day course, blood samples were drawn before and 2 h after each morning dose. In Group I patients, substantial plasma theophylline concentrations were seen only after the loading dose. Thereafter, the mean concentrations before or 2 h after the morning doese were always less than 4.0 µg/ml. Trough concentrations were usually below 2.0 µg/ml. In contrast patients in Group II achieved substantially higher plasma theophylline concentrations, with mean peak concentrations always 10 µg/ml or greater, and trough concentrations greater than 5 µg/ml on at least one occasion in every subject. The elimination half-lives after chronic administration in both groups were not significantly different from those obtained after single doses. Mean drug accumulation, measured as AUC_ss/AUC₁, was 0.87±0.07 in Group I and 0.72±0.14 in Group II, indicating that accumulation had not occurred with either regimen. The mean increase in FEV₁ 2 h after the administration of a single dose was 19.2% after 375 mg and 16.7% after 250 mg. These results indicate that the recommended dosage regimen for microcrystalline theophylline preparation (375 mg stat and 125 mg 4 times daily) produces inadequate plasma theophylline concentrations: 250 mg 4 times daily would appear to be likely to result in satisfactory theophylline levels in more patients.     

司帕沙星及洛美沙星对老年慢性阻塞性肺病患者茶碱缓释片药动学的影响

目的　研究司帕沙星及洛美沙星对老年慢性阻塞性肺病(COPD)患者茶碱缓释片药动学的影响。方法　36例老年COPD患者口服茶碱缓释片10 0mg ,q8h×9d ,d 4起Ⅰ组18例合用司帕沙星片2 0 0mg ,qd ;Ⅱ组18例合用洛美沙星胶囊4 0 0mg ,q12h。于d 4、10采集血样,采用荧光偏振免疫法检测茶碱的血药浓度,用PKBP N1程序求得药动学参数。结果　合用司帕沙星后茶碱血药浓度较合用前明显升高(P <0 .0 1) ,AUC及cmax差异有高度统计学意义(P <0 .0 1) ;而合用洛美沙星后其血药浓度较合用前稍有升高(P >0 .0 5 ) ,药动学参数除tmax有统计学意义(P <0 .0 5 )外,其余的变化均无统计学意义。结论　司帕沙星对茶碱的药动学有显著性影响,而洛美沙星对茶碱的药动学情况基本上无明显的影响。     

盐酸加替沙星对兔体内茶碱药动学的影响

目的:研究盐酸加替沙星对家兔体内茶碱药动学的影响.方法:6只家兔于第1,6天单次静脉注射氨茶碱10 mg·kg-1,第2～6天灌服盐酸加替沙星20 mg·kg-1,qd.用氨茶碱后各时间点采静脉血,测定茶碱血清浓度,数据用3P97药动学软件处理,计算参数,并用t检验进行统计处理.兔血清氨茶碱浓度以HPLC法测定.结果:氨茶碱在兔体内的药动学过程呈二室模型,t1/2分别为(0.21±0.04)h和(0.33±0.21 )h;t1/2β分别为(4.4±0.8)h和(4.8±1.1)h ;AUC分别为(72.9±10.6)g·h·mL-1和(80.7±20.3)g·h·mL-1;CL分别为(139.7±21.7)mL··h-1·kg-1和(131.4±36.3)mL·h-1·kg-1;V(c)分别为(495.3±26.55)mL·kg-1和(462.86±34.71)mL·kg-1.结论:所有参数经双侧t检验,差异无显著性(P>0.05),合用加替沙星对家兔体内氨茶碱药动学无影响.     

茶碱在老年慢性阻塞性肺疾病患者中的群体药动学

目的：建立茶碱在老年慢性阻塞性肺疾病患者中的群体药动学（PPK）模型,并获取药动学参数,为临床制定个体化给药方案提供参考。方法：收集2014年4—12月某院诊断为慢性阻塞性肺疾病应用茶碱治疗的68例老年患者的血药浓度监测数据及临床资料,运用非线性混合效应模型法（NONMEN）定量分析性别、年龄、体质量及肝肾功能等因素对药动学参数的影响,最终建立PPK模型。采用拟合优度、自举法和可视化检验对最终模型的性能进行内部验证。结果：茶碱的药动学符合一室模型,最终模型公式为：CL=θ_CL×（WT/63）^θWT×exp（η_CL）,V=θ_V×exp（η_V）,其中的协变量为体质量,模型CL和V的群体典型值分别为0.849 L·h^-1,13.7 L。拟合优度、自举法和可视化检验的评价结果表明最终模型稳定,预测结果可靠。结论：建立的PPK模型能较好地描述茶碱在老年慢性阻塞性肺疾病患者中的药动学特点,患者体质量对参数CL有显著性影响。     

住院病人茶碱群体药物动力学NONMEM法分析

对72名临床病人进行茶碱群体药物动力学研究,用NONMEM法分析了多种因素对茶碱药物动力学过程的影响。结果表明:在18至77a范围内,年龄对清除率(Cl)有显著性影响,每岁降低1.25％;长期多剂量服用茶碱的哮喘患者,Cl降低26.8％;OLD时Cl降低33.9％;合并用Ac-SPM时Cl略有降低,但影响不大;性别和体重对Cl无显著影响。     

新生儿氨茶碱药动学研究

本文采用荧光偏振免疫分析法测定１２例新生儿血中茶碱浓度，氨茶碱剂量按５ｍｇ／ｋｇ恒速静脉滴注。经时采样，测得数据，经分析药时曲线拟合呈一室模型，平均清除速度常数０．０３７±０．００８ｈ￣（－１），平均消除半衰期１９±４ｈ，平均表观分布容积０．８２±０．１４Ｌ／ｋｇ，平均清除率３０±５ｍｌ／（ｈ·ｋｇ）。消除半衰期最大相差２．１倍，显示明显个体差异。     

Sex-related differences in theophylline pharmacokinetics

Summary Theophylline pharmacokinetic parameters were compared in healthy males and healthy premenopausal females who were matched for age and smoking status. Twenty-four subjects (including five smokers and seven non-smokers of each sex) received a single dose of aminophylline 6 mg·kg^–1, orally or by intravenous infusion. Theophylline half-life was significantly shorter in female non-smokers (FNS) versus male non-smokers (MNS), (FNS=6.0 h; MNS=9.3 h), and in female smokers (FS) versus male smokers (MS), (FS=4.6 h; MS=6.3 h). Total body clearance was significantly different in FNS versus MNS, (FNS=43.8 ml·min^–1·^–1.73 m^–2; MNS=37.4 ml·min^–1·1.73 m^–2), but did not reach statistical significance in FS vs. MS, (FS=64.2 ml·min^–1·l^–1·1.73 m^–2; MS=53.1 ml·min^–1·1.73 m^–2). Volume of distribution did not differ significantly between groups.Sex differences in theophylline pharmacokinetics exist and may reflect differences in drug metabolism.     

Personality and theophylline pharmacokinetics

Summary Thirteen volunteers received an iv dose of theophylline followed by blood sampling for 8 h to calculate pharmacokinetic parameters. Ten patients with asthma undergoing chronic dosing with slow release aminophylline underwent 12 h of blood sampling to calculate theophylline clearance. Both groups completed an Eysenck Personality Inventory (EPI) from which was derived scores for neuroticism (N) and extroversion (E). Using multiple regression analysis no independent effect of either N or E score on theophylline clearance or half-life could be demonstrated.     

Absolute bioavailability of theophylline from a sustained-release formulation using different intravenous reference infusions

Summary The effect of different intravenous infusions on the absolute bioavailability of theophylline from a sustained-release formulation has been investigated. Oral administration of 750 mg theophylline (2 capsules Euphylong 375) was referenced to intravenous aminophylline infusions corresponding to 506 mg theophylline over 8 h (63 mg·h^–1) in Study 1, and to 749 mg theophylline over 14 h in Study 2. A reduction in the infusion rate from 69 to 33 mg·h^–1 was made in Study 2 after 8 h in order to mimic the concentration/time profile of the oral formulation as closely as possible. The absolute bioavailability was 100 (89, 115) % in Study 1 and 88 (73, 105) % in Study 2.The lower clearance values and, as a consequence, the lower bioavailability ratios observed with the higher intravenous dose, although not significant, indicate that the absolute bioavailability of theophylline might appear to depend on the choice of the intravenous reference standard.     

Pharmacokinetics of theophylline in patients following short-term intravenous infusion

Summary Serum theophylline concentrations after intravenous administration of a new short-term infusion (Euphyllin^® Kurzzeitinfusion) were measured in 50 out-patients with chronic obstructive airways disease (COAD). An intravenous infusion of theophylline ethylenediamine 480 mg (corresponding to approximately 350 mg anhydrous theophylline) in 50 ml isotonic solution was given in 20 min. Blood samples were taken beforehand and 25 to 30 min and 1, 3 and 6 h after starting the infusion. 86% of the patients had a one-hour serum level in the therapeutic range of 8–20 mg/l, and 2 h later, this was true of 64% of the patients. The short-term infusion was well tolerated, even in cases with unknown high pre-infusion serum levels. Pertinent pharmacokinetic parameters were determined, such as total body clearance, apparent volume of distribution, and half-life of elimination. Geometric mean and 95%-confidence limits, derived from the log-normal distribution of these parameters, were: Cl=0.044 (0.018–0.109) l/h/kg ideal body weight, V_d=0.451 (0.258–0.789) l/kg ideal body weight, and t_1/2(el)=7.1 (2.6–19.1) h.     

氟罗沙星对肺心病人体内茶碱药物动力学的影响

目的：本文研究氟罗沙星对肺心病人体内茶碱药物动力学的影响，为临床合理用药提供依据。方法：应用荧光偏振免疫法分别测定了８名肺心病患者单独静脉滴注氨茶碱及合用氟罗沙星达稳态后茶碱的血药浓度。结果：氟罗沙星明显延长了茶碱的半衰期（Ｐ＜０．０１），使茶碱稳态血药浓度明显升高（Ｐ＜０．０１），清除率降低（Ｐ＜０．０１），分布容积亦明显增大（Ｐ＜０．０１）。结论：氟罗沙星能抑制茶碱的正常代谢，临床上两药合用时应注意氨茶碱剂量的调整。     

稳态时加替沙星对茶碱在家兔体内药动学的影响

目的 :研究稳态时加替沙星对茶碱在家兔体内药动学的影响。方法 :采用自身对照法 ,HPLC法平行监测合用药前后茶碱的血药浓度 ,通过PKBP N1软件拟合茶碱的药动学参数 ,并做统计学比较。结果 :合并用药前后茶碱的血药浓度AUC差异有显著性 (P <0 .0 5 ) ,合用后茶碱的血药浓度显著提高 ,峰时Tmax提前 ,吸收速率Ka 变大 ,消除半衰期T1 / 2 β相应延长 ,消除率相应减少。结论 :加替沙星能延缓茶碱在体内的代谢 ,提示合并用药时应对茶碱进行血药浓度监测 ,防止因茶碱代谢减慢而引起蓄积中毒。     

Effect of alosetron on theophylline pharmacokinetics

AIMS: To examine the potential for alosetron to alter the pharmacokinetics of theophylline by inhibiting its metabolism, as suggested by in vitro and in vivo effects on CYP1A2 activity. METHODS: Ten healthy female volunteers received theophylline 200 mg twice daily alone for 8 days and with alosetron 1 mg twice daily for 15 days in this randomized, placebo-controlled, two-way-crossover study. RESULTS: Alosetron had no significant effect on theophylline plasma concentrations (Cmax approximately 9 microg ml(-1), AUC approximately 90 microg ml(-1) h) or oral formation clearance of three major metabolites produced via CYP1A2: 3-methylxanthine, 1-methylurate and 1,3-dimethylurate (5, 7 and 16 ml min(-1), respectively). Concomitant administration of alosetron and theophylline was well tolerated. CONCLUSIONS: The absence of a clinical drug interaction involving inhibition of theophylline metabolism by alosetron was not predicted by in vitro and in vivo metabolic probe data.     

甲氟哌酸对茶碱在家兔体内药物动力学的影响

目的：在家兔体内观察甲氟哌酸对茶碱的药物动力学的影响。方法：动物分为２组，第１组静注茶碱１２ｍｇ·ｋｇ－１，第２组静注茶碱１２ｍｇ·ｋｇ－１和甲氟哌酸２０ｍｇ·ｋｇ－１，用高效液相法测定茶碱的血药浓度，计算机拟合房室模型并计算药物动力学参数。结果：茶碱的药时曲线符合二室模型，合用甲氟哌酸后，茶碱的药时曲线消除相血药浓度显著高于单用茶碱；茶碱的消除半衰期Ｔ１／２β和曲线下面积ＡＵＣ明显增大；机体清除率ＣＬ明显降低，两组之间有显著性或非常显著性差异。结论：甲氟哌酸能延缓茶碱在兔体内的清除，提示合并用药时应对茶碱进行临床给药监测。     

培氟沙星及诺氟沙星对慢性阻塞性肺疾病患者氨茶碱药物动力学的影响

目的量化地研究培氟沙星(PFLX)及其代谢产物诺氟沙星(NFLX)对肺阻塞性疾病患者氨茶碱(Ami)药物动力学的影响.方法18例慢性阻塞性肺疾病(COPD)患者poAmi100mg,q8h,d4起第Ⅰ组(9例)加服PFLX400mg,q12h;第Ⅱ组(9例)加服NFLX400mg,q12h.至d9,以高效液相色谱色(HPLC)平行监测合用前后茶碱(Theo)的经时血浓,拟合Theo药物动力学参数并做统计学比较.结果与合用前相比,第Ⅰ组患者血清中Theo浓度显著增高(P<0.05),消除半衰期非常显著性延长(P<0.01),清除率显著下降(P<0.05);第Ⅱ组患者血清中Theo浓度也有所增加,消除半衰期相应延长,清除率相应减少,但均无统计学差异(P>0.05).结论合用PFLX对Ami的消除动力学有显著性抑制,临床合用时应注意Theo的血浓监测,防止Ami因代谢减慢而引起蓄积中毒NFLX与Ami合用则相对安全.     

No effect of chloroquine on theophylline pharmacokinetics in the rat

The immediate and delayed effects of chloroquine on theophylline kinetics were investigated in rats pretreated with chloroquine diphosphate (45 mg kg⁻¹) or saline intraperitoneally. One hour or 4 days after chloroquine, theophylline (10 mg kg⁻¹) was administered intravenously. Compared with the control animals pretreated with saline, the disposition parameters of theophylline was not altered after pretreatment with chloroquine. Chloroquine did not affect the in vivo metabolism of theophylline in the laboratory rat. A possible decrease in theophylline's volume of distribution at 4 days, but not immediately, after administration of chloroquine was suggested, although this just failed to achieve statistical significance (p = 0.055). Being marginal, it is unlikely to be of clinical concern. It is concluded that, judged from these animal data, there is no evidence of a drug–drug pharmacokinetic interaction for the combination of chloroquine and theophylline. © 1998 John Wiley & Sons, Ltd.     

司帕沙星对老年慢性阻塞性肺病患者茶碱缓释片药动学的影响

目的:研究司帕沙星对老年慢性阻塞性肺病(COPD)患者茶碱缓释片药动学的影响.方法:采用荧光偏振免疫法检测18例老年COPD患者联用司帕沙星前后茶碱各时点的血药浓度,用PKBP-N1程序求得药动学参数,并作统计学分析.结果:联用司帕沙星(200mg,qd)5 d后血药浓度较联用前均有升高(P＜0.01),药动学参数曲线下面积(AUC)及最大峰浓度(Cmax)差异有极显著性(P＜0.01).结论:司帕沙星以200 mg,qd给药对茶碱的药动学有显著性影响,临床联用时应监测茶碱血药浓度,防止茶碱因代谢减慢而引起中毒.     

Population pharmacokinetics of theophylline during paediatric extracorporeal membrane oxygenation

AIMS: To determine the population pharmacokinetics of theophylline during extracorporeal membrane oxygenation (ECMO) from routine monitoring data. METHODS: Retrospective data were collected from 75 term neonates and children (age range 2 days to 17 years) receiving continuous infusions of aminophylline (mean rate 9.2 +/- 2.6 micro g kg-1 min-1) during ECMO. A total of 160 plasma concentrations (range 1-8 per patient), sampled at time intervals ranging from 10 h to 432 h, were included. Population PK analysis and model building were carried out using WinNonMix Professional (Version 2.0.1). Cross-validation was used to evaluate the validity and predictive accuracy of the model. RESULTS: A one-compartment model with first order elimination combined with an additive error model was found to best describe the data. Of the covariables tested, bodyweight significantly influenced clearance and volume of distribution, whereas age was an important determinant of clearance, as adjudged by the differences in the -2 x log likelihood (P < 0.005) and the residual error value. The final model parameters were estimated as: clearance (l h-1) = 0.023 x bodyweight (kg) + 0.000057 x age (days) and volume of distribution (l) = 0.57 x bodyweight (kg). The interindividual variability in clearance and volume of distribution was 38% and 40%, respectively. The residual error corresponded to a standard deviation of 3.6 mg l-1. Cross-validation revealed a median (95% confidence interval) model bias of 9.4% (2.9, 16.5%) and precision of 29.5% (24.8, 36.0%). CONCLUSIONS: The estimated clearance is significantly lower, and volume of distribution higher, than previously reported in non-ECMO patients of similar age. These differences are probably a result of the expanded circulating volume during ECMO and altered renal and hepatic physiology in this critically ill group. Large interindividual variability reflects the heterogeneous nature of patients treated on ECMO.