渗透压微泵恒速给药丙戊酸在小鼠体内的时间药物动力学

以渗透压微泵植入小鼠皮下恒速给予丙戊酸钠，在达到理论稳态浓度时间后，血浆药浓呈昼夜变化，白昼高于夜间，峰值位于明期末。药动学研究揭示丙戊酸血药浓度的昼夜差异可能与其清除率及分布容积的昼夜变化有关。     

庆大霉素不同给药方案的药代动力学和肾功能损害的实验研究

目的研究庆大霉素(GTM)不同时辰给药方案对大鼠肾功能损害、血药浓度和药动学参数的影响。方法①大鼠分6组:对照组、时辰每日单次给药组[N(活动期给药)100组、D(休息期给药)100组,分别于1:00和13:00给药100mg·kg-1,im]、时辰每日2次不等量给药组和传统每日2次等量给药组(N90+D10组、N70+D30组、N50+D50组,每日1∶00和13∶00分2次im90mg·kg-1+10mg·kg-1、70mg·kg-1+30mg·kg-1、50mg·kg-1+50mg·kg-1)。各组分别于给药d1、10和20测定血清肌酐(Cr)、血清尿素氮(BUN)。②给药后0.25、0.5、1、2、5和8h分别于眼眶取血,测定血药浓度,给药d10、20重复上述采血过程。绘制药时曲线,计算药动学参数。结果①肾功能损害:给药d10,N50+D50组Cr和BUN水平最高,与给药d1和同期对照组相比差异有显著性(P<0.05);N100组最低,与同期对照组相比差异有显著性(P<0.05)。血药浓度:给药d10,N100组和D100组峰浓度差异有显著性(P<0.05)。给药d20,N50+D50组峰浓度高于两次不等剂量组峰浓度,但差异无显著性。③药动学参数:给药d20,N50+D50组CLs最小,N100组最大,给药d1、10、20,N100组T12最短,N50+D50组T12最长(P<0.05)。结论在时辰给药方案中,GTM以活动期单次给药肾功能损害最小,血药峰浓度低,T12最短,CLs最大。     

大鼠体内中毒剂量氨茶碱的时辰药物动力学

２０只大鼠在标准明暗周期（明期：暗期＝１２ｈ∶１２ｈ）下饲养１周，自由进食进水，并随机分为２组，９∶００组于上午９∶００给予氨茶碱５０ｍｇ／ｋｇ，ｉｐ，于用药后０．５，１．０，１．５，３．０，６．０，７．５ｈ剪尾取血，高效液相色谱法检测血药浓度。２１∶００组于液间２１∶００给药，方法同前。结果：（１）２１∶００组血药浓度较９∶００组高，Ｃｍａｘ大；Ｔ１／２小，Ｋｅ大，其中Ｔ１／２相差达１．４５倍；２１∶００组ＡＵＣ０－７．５ｈ大于９∶００组，但ＡＵＣ（０－∞ｈ）小于９∶００组。（２）本研究中大鼠血药浓度是人类最高限浓度的２～３倍，用药后大鼠呈中毒表现，由于消除快速，ｃ－ｔ曲线仍呈线性，与人类不同。     

硝苯吡啶在家兔体内的时辰药代动力学

目的:观察硝苯吡啶(NF)在家兔体内不同给药时间药代动力学特征。方法:用HPLC法测定不同时间单剂量给药后NF在家兔体内药代动力学。结果:NF在8:00给药AUC,tmax,Cmax分别为974.69μg/(L·h),0.91h,162.15μg/L。在20:00给药分别为536.29μg/(L·h),1.35h,93.61μg/L。2个时间给药的药动学参数差异有统计学意义(P<0.01)。家兔体内NF的药代动力学规律均符合血管外给药一级吸收单室模型,并呈现明显的时间依赖性变化。结论:清晨给药可提高NF的生物利用度。     

Evening dosing is associated with higher plasma concentrations of pranlukast, a leukotriene receptor antagonist, in healthy male volunteers

Aims To study the magnitude of differences in the pharmacokinetics of pranlukast, after morning and evening administration.
Methods Pranlukast (300  mg) was administered to 12 healthy male volunteers on two separate occasions, either in the morning or evening. Both doses were given 30  min after a standard high fat content meal. Blood samples were collected up to 18  h postdose. Plasma was assayed by high performance liquid chromatography. Standard pharmacokinetic and statistical analyses were performed.
Results Statistically significant ( P <0.05) increases were noted in AUC(o, t ) (56%) and t _max (2.5  h) after evening administration. C _max was 14% higher after evening dosing (95% C.I. 0.71–1.84).
Conclusions Pranlukast bioavailability is apparently increased after evening dosing as compared with morning administration. Higher night-time and early morning plasma concentrations may confer additional therapeutic benefit at a time when asthmatics are at greatest risk of developing bronchospasm.     

Circadian rhythms in the CNS and peripheral clock disorders: chronopharmacological findings on antitumor drugs

The effectiveness and toxicity of antitumor drugs vary depending on dosing time associated with the 24-h rhythms of biochemical, physiological, and behavioral processes under the control of the circadian clock. Such chronopharmacological phenomena are influenced by not only the pharmacokinetics but also pharmacodynamics of medications. For example, the antitumor effect and/or toxicity of irinotecan hydrochloride, interferon, and antiangiogenic agents vary depending on the dosing time associated with the 24-h rhythm of their target enzyme, receptor, protein, and pharmacokinetics. Many of them are controlled by clock genes. Chronotherapy is especially relevant when the risk and/or intensity of the symptoms of disease vary predictably over time. In a randomized multicenter trial involving patients with previously untreated metastases from colorectal cancer, the chronomodulated infusion of oxaliplatin, fluorouracil (5-FU), and folinic acid is compared with a constant-rate infusion method. Side effects such as stomatitis, peripheral sensory neuropathy are lower and the objective response is higher in the chronotherapy as compared with the fixed-rate infusion. The merit of chronomodulated infusion is supported by the 24-h rhythm of DNA synthesis and the activity of dehydropyrimidine dehydrogenase, which brings about the intracellular catabolism of 5-FU. Although interferon (IFN) also alters the clock function, the disruptive effect of IFN on clock function can be overcome by devising a dosing regimen that minimizes adverse drug effects on clock function. Thus one approach to increasing the efficiency of pharmacotherapy is the administration of drugs at times at which they are most effective and/or best tolerated.     

Circadian phase dependent pharmacokinetics of L-dopa, its main metabolites (3-OMD, HVA, DOPAC) and carbidopa in rats

Summary— This study aims to evaluate whether or not the kinetics of L-dopa, its main metabolites (3-O-methyldopa, 3-OMD, homovanilic acid, HVA and 3,4-dihydroxyphenylacetic acid, DOPAC) and carbidopa, vary according to the 24-hour scale in rats. Four groups of seven adult male Wistar AF EOPS rats were used for these experiments; each group received L-dopa (200 mg·kg⁻¹ ip) and carbidopa (20 mg·kg⁻¹ ip) at 1000, 1600, 2200 or 0400 hours. L-dopa, 3-OMD, DOPAC, HVA and carbidopa were simultaneously determined by specific ion-pair reversed-phase high performance liquid chromatography with electrochemical detection. A temporal variation of the kinetics of both L-dopa and carbidopa was demonstrated with higher plasma clearance and lower area under concentration curve after the administration at 2200 hours. Moreover, a temporal variation of the metabolism of L-dopa was indirectly documented by temporal variation in kinetics of 3-OMD, DOPAC and HVA.     

Circadian changes in the pharmacokinetics and cardiovascular effects of oral propranolol in healthy subjects

Summary Four subjects were synchronized with activity from 07 to 23 h and were given a single oral dose of 80 mg racemic propranolol at fixed times (08, 14, 20 and 02 h) at weekly intervals.ANOVA revealed significant circadian changes in the peak propranolol concentration (C_max), with a maximum at 08 h and a minimum at 02 h after drug intake; t_max was not dependent on the circadian phase. The elimination half-life varied significantly with the time of day, being shortest at 08 h (3.3 h) and longest at 20 h (4.9 h). The stereospecificity of the propranolol pharmacokinetics was not dependent on the time of drug intake. No circadian variation was found in the maximum decrease in heart rate, but the time to peak effect was dependent on the time of drug intake; t_max was 2.3 h at 08 h and 7.0 h at 02 h. Thus, the time to peak drug concentration did not coincide with the time to peak effect on heart rate at different times of day. Circadian changes were also found in the systolic blood pressure and in the double product.The results show a significant daily variation in the pharmacokinetics and cardiovascular effects of propranolol. However, chronokinetics cannot explain the circadian changes in the effects of the drug. It is concluded that circadian variation in sympathetic tone and vascular reactivity is mainly responsible for the circadian changes in the effects of propranolol.     

顺铂在家兔体内的时间药动学

目的　研究顺铂在家兔体内药代动力学的时间节律特征。方法　实验动物饲养在标准环境中,分别于昼夜不同时辰一次给药,以原子吸收光谱法测定给药后不同时刻血中铂浓度,并将通过３ Ｐ８７ 程序计算所得的主要药动学参数按平均余弦法进行处理。结果和结论　顺铂的主要药动学参数呈一定昼夜变化,其中消除相半衰期（ Ｔ１２ β） 、表观分布容积（ Ｖｄ） 、曲线下面积（ Ａ Ｕ Ｃ） 、清除率（ Ｃ Ｌ） 等波动较大,峰、谷值之间具显著或非常显著差异。上述各参数昼夜节律峰值期分别在０２ ：１３ 、０４ ：４５ 、００ ：３７ 和１３ ：１０     

Clinical Study on Chronopharmacokinetics of Digoxin in Patients with Congestive Heart Failure

Digoxinisamediumspeeddigitalis,oneofmostcommonlyusedoraldrugsinclinicalpracticeforthetreatmentofcongestiveheartfailure(CHF).Thetherapeuticdosageisveryclosetothetoxicdosage,sotherangeofthetherapeuticdosageiswithinanarrowlimit.Althoughtheserumdigoxinconcentrationtestshavebeenconductedforpatientsonthedigitalisduringrecentlyyears,thedeathrateofdigoxinintoxicationwasashighas4.6%["Zj.Inordertofindaguidanceforrationaluseofdigoxinandprovideareferencefortheclinicaltreatment,weconductedself~controlled…