BACKGROUND & AIMS: We have determined the pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of rocuronium in infants and children. We studied infants (n = 5, 0.1-0.8 yr) and children (n = 5, 2.3-8 yr), ASA II, in the ICU while undergoing artificial ventilation under i.v. anaesthesia with an arterial cannula in situ and the EMG of the adductor pollicis muscle was monitored. Rocuronium 0.06 (infants) and 0.09 (children) mg kg-1 min-1 was given i.v. over +/- 5 min until 85% neuromuscular block was obtained. Arterial blood samples were obtained over 240 min. Plasma concentrations were measured by HPLC. Pharmacokinetic-dynamic variables were calculated using the Sheiner model and the Hill equation. Statistical analysis was performed using the Mann-Whitney U test (P < 0.05). The mean administered dose was 0.32 (SD 0.08) mg kg-1 and 0.4 (0.1) mg kg-1 for infants and children, respectively. Infants differed from children in plasma clearance (4.2 (0.4) vs 6.7 (1.1) ml min-1 kg-1), distribution volume at steady state (231 (32) vs 165 (44) ml kg-1), mean residence time (56 (10) vs 26 (9) min), concentration in the effect compartment at 50% block (1.2 (0.4) vs 1.7 (0.4) mg litre-1) and the slope of the concentration-effect relationship (5.7 (1.3) vs 3.9 (0.5)). Calculated mean ED90 values were 0.26 and 0.34 mg kg-1 for infants and children, respectively. The time course of neuromuscular block after equipotent doses did not differ.

背景与目标： 我们已经确定了罗库溴铵在婴儿和儿童中的药代动力学和药代动力学-药效学关系。我们研究了在ICU中进行人工通气的婴儿 (n = 5，0.1-0.8岁) 和儿童 (n = 5，2.3-8岁) ASA II。使用原位动脉插管进行麻醉，并监测内收肌的EMG。静脉注射罗库溴铵0.06 (婴儿) 和0.09 (儿童) mg kg-1 min-1。超过 +/- 5分钟，直到获得85% 神经肌肉阻滞。在240分钟内获得动脉血样本。通过HPLC测量血浆浓度。使用Sheiner模型和Hill方程计算药代动力学变量。使用Mann-Whitney u检验进行统计分析 (P <0.05)。婴儿和儿童的平均施用剂量分别为0.32 (SD 0.08) mg kg-1和0.4 (0.1) mg kg-1。婴儿与儿童的血浆清除率 (4.2 (0.4) vs 6.7 (1.1) ml min-1 kg-1)，稳态分布体积 (231 (32) vs 165 (44) ml kg-1)，平均停留时间 (56 (10) 对26 (9) min)，在50% 块处的效应室中的浓度 (1.2 (0.4) 对1.7 (0.4) mg升-1) 和浓度-效应关系的斜率 (5.7 (1.3) 对3.9 (0.5))。婴儿和儿童的平均ED90值分别为0.26和0.34 mg kg-1。等效剂量后神经肌肉阻滞的时间过程没有差异。

BACKGROUND & AIMS: :A three-way crossover study in 27 human volunteers was conducted to characterize the pharmacokinetics and to assess the dose proportionality of 100 mg, 200 mg and 300 mg strengths of a novel once-a-day tramadol controlled-release tablet (Tramadol Contramid OAD) following single-dose administration. Serial blood samples were collected at predefined timepoints over a 48 h period and racemic tramadol and O-desmethyltramadol concentrations in plasma were determined using a validated LC-MS/MS method. Pharmacokinetic parameters were derived using noncompartmental methods. Following dose normalization and logarithmic transformation of concentration-dependent parameters, the results were compared using analysis of variance (ANOVA). The residual variability thereby obtained was used to construct 90% classical confidence intervals. The two one-sided tests procedure was used for all pairwise comparisons. Dose proportionality was concluded since the 90% CI for the ratio of geometric means was included in the acceptance range of 0.80-1.25 for all comparisons.

背景与目标： : 在27名人类志愿者中进行了一项三向交叉研究，以表征药代动力学并评估100 mg，200 mg和300 mg的剂量比例。单剂量给药后的新型曲马多控释片 (曲马多对照OAD) 的强度。在48小时内的预定时间点收集连续血液样本，并使用经过验证的lc-ms/MS方法测定血浆中外消旋曲马多和O-去甲基曲马多的浓度。药代动力学参数是使用非隔室方法得出的。在剂量归一化和浓度相关参数的对数转换之后，使用方差分析 (ANOVA) 比较结果。由此获得的残差变异性用于构建90% 经典置信区间。所有成对比较均使用两个单侧测试程序。由于几何平均值比的90% CI被包括在所有比较的0.80-1.25的接受范围内，因此得出了剂量比例。

BACKGROUND & AIMS: BACKGROUND:Different opioids have different delays (hysteresis) between their concentrations in blood and their cerebral effects. Possible mechanisms include differences in their rate of penetration into the brain and differences in their distribution volume in the brain. There have been few in vivo studies of the cerebral kinetics of opioids to differentiate these mechanisms.

METHODS:The cerebral kinetics of meperidine and alfentanil were examined using conscious sheep that were fitted with long-term monitoring equipment to measure relative changes in cerebral blood flow and opioid concentration gradients across the brain through frequent sampling of arterial and sagittal sinus blood. The data were compared using hybrid physiologic modeling with membrane-limited (consistent with mechanism 1) and flow-limited (consistent with mechanism 2) models of cerebral kinetics.

RESULTS:Alfentanil had a variable effect on relative cerebral blood flow, whereas meperidine induced a transient increase. The arteriovenous concentration gradients were small after alfentanil but large after meperidine. The flow-limited model gave acceptable descriptions of observed sagittal sinus concentrations for alfentanil and meperidine, whereas the membrane-limited model collapsed to a flow-limited model. The half-lives of equilibrium between blood and brain were 6.3 and 0.8 min for meperidine and alfentanil, respectively:

CONCLUSIONS:The rate of penetration of both opioids into the brain was rapid and not rate-limiting. Large differences in the cerebral distribution volume of meperidine and alfentanil accounted for the respective delays in their peak brain concentration relative to blood.

背景与目标： 背景 : 不同的阿片类药物在血液中的浓度与大脑作用之间具有不同的延迟 (滞后)。可能的机制包括它们渗透到大脑的速率的差异以及它们在大脑中的分布体积的差异。关于阿片类药物的脑动力学的体内研究很少，可以区分这些机制。
方法 : 使用配备了长期监测设备的有意识的绵羊检查了哌替啶和阿芬太尼的脑动力学，以通过频繁采样动脉和矢状窦血来测量整个大脑中脑血流量和阿片类药物浓度梯度的相对变化。使用混合生理模型与脑动力学的膜受限模型 (与机制1一致) 和流量受限模型 (与机制2一致) 进行数据比较。
结果 : 阿芬太尼对相对脑血流量有不同的影响，而哌替啶诱导了短暂的增加。阿芬太尼后动静脉浓度梯度较小，而哌替啶后动静脉浓度梯度较大。限流模型对观察到的阿芬太尼和哌替啶的矢状窦浓度给出了可接受的描述，而膜限流模型崩溃为限流模型。对于哌替啶和阿芬太尼，血液和大脑之间的平衡半衰期分别为6.3和0.8分钟:
结论 : 两种阿片类药物进入大脑的速率是快速的，而不是限速。哌替啶和阿芬太尼的脑分布体积差异很大，导致其峰值脑浓度相对于血液的延迟。

BACKGROUND & AIMS: AIMS:To characterize the population pharmacokinetics of tipifarnib. METHODS:A total of 1083 subjects treated orally with a solution, capsule or tablet formulations of tipifarnib, given as a single dose or as multiple twice-daily doses (range 25-1300 mg) were combined with data from 1, 2 and 24 h intravenous infusions. A total of 3445 concentrations in the index data set were fitted by an open three-compartment linear disposition model with sequential zero-order input into the depot compartment, followed by a first-order absorption process, and lag time, using NONMEM V. The effect of patient covariates on tipifarnib pharmacokinetics was explored. The model was evaluated using goodness of fit plots and relative error measurements for 3894 concentrations in the test data set. Computer simulations were undertaken to evaluate the effect of covariates on tipifarnib pharmacokinetics. RESULTS:Tipifarnib oral bioavailability (26.7%) did not differ between the formulations. The absorption rate from the solution was faster than from the solid forms. Whereas the absorption rate and systemic clearance were more rapid in healthy subjects, the extent of absorption and the steady-state volume of distribution were comparable in cancer patients and healthy subjects. Systemic clearance in cancer patients (21.9 l h-1) exhibited a statistically significant relationship with total bilirubin. The typical volume of the central compartment in cancer patients (54.6 l 70 kg-1) was directly proportional to body weight. The clinical relevance of these covariates in cancer patients is questionable as there was a substantial overlap in simulated concentration-time profiles across a wide range of covariate values. CONCLUSIONS:A population PK approach has been used to integrate data gathered during clinical development and to characterize the pharmacokinetics of tipifarnib. Individualization of dose based on body weight or total bilirubin concentration in adult cancer patients is not warranted.

背景与目标：

BACKGROUND & AIMS: :Pharmacological response depends on multiple factors and one of them is sex-gender. Data on the specific effects of sex-gender on pharmacokinetics, as well as the safety and efficacy of numerous medications, are beginning to emerge. Nevertheless, the recruitment of women for clinical research is inadequate, especially during the first phases. In general, pharmacokinetic differences between males and females are more numerous and consistent than disparities in pharmacodynamics. However, sex-gender pharmacodynamic differences are now increasingly being identified at the molecular level. It is now even becoming apparent that sex-gender influences pharmacogenomics and pharmacogenetics. Sex-related differences have been reported for several parameters, and it is consistently shown that women have a worse safety profile, with drug adverse reactions being more frequent and severe in women than in men. Overall, the pharmacological status of women is less well studied than that of men and deserves much more attention. The design of clinical and preclinical studies should have a sex-gender-based approach with the aim of tailoring therapies to an individual's needs and concerns.

背景与目标： : 药理反应取决于多种因素，其中之一是性别。有关性别对药代动力学的特定影响以及许多药物的安全性和有效性的数据开始出现。然而，招募女性进行临床研究是不够的，尤其是在第一阶段。通常，男性和女性之间的药代动力学差异比药效学差异更多且一致。然而，性别-性别药效学差异现在越来越多地在分子水平上被发现。现在甚至变得很明显，性别会影响药物基因组学和药物遗传学。已经报告了几个参数的性别相关差异，并且一直显示女性的安全性较差，女性的药物不良反应比男性更为频繁和严重。总体而言，女性的药理状况比男性研究得少，值得更多关注。临床和临床前研究的设计应采用基于性别的方法，目的是根据个人的需求和关注点定制疗法。

BACKGROUND & AIMS: INTRODUCTION:Isoproterenol is a non-selective β receptor agonist, which is a drug approved for bradycardia and bronchial asthma in many countries. Recently, isoproterenol has been reported to have the potential as a drug for the treatment of Alzheimer's disease by inhibiting the aggregation of tau protein. Isoproterenol is a highly potent drug causing increases in heart rates even when its plasma concentration is very low. Thus, it is critical to know if potentially effective therapeutic levels of isoproterenol can be achieved, maintaining safe plasma levels without any untoward pharmacological effects. The purpose of the study is to investigate the brain pharmacokinetics and biodistribution of 11C-labeled isoproterenol in rodents. METHODS:We performed positron emission tomography (PET) brain imaging and biodistribution studies of [11C]isoproterenol. 120-min scans with arterial blood sampling were performed in rats. Additionally, plasma and brain homogenates were analyzed with radio-HPLC to characterize its metabolite profiles. As a measure of [11C]isoproterenol brain uptake, total distribution volumes were determined by a pharmacokinetic compartment model. Biodistribution of [11C]isoproterenol was investigated in mice at six-time points from 1-min to 90-min after injection. RESULTS:We found a modest brain uptake of [11C]isoproterenol. Its brain pharmacokinetics showed that the concentration of isoproterenol in the brain at equilibrium was about two-fold higher than in the plasma (total distribution volumes 2.0 ± 0.2 cm3/mL). Only unmetabolized isoproterenol was detected in the brain at 30 min after injection, although isoproterenol was rapidly metabolized in plasma. The biodistribution study showed that isoproterenol and its metabolite are excreted mainly via the urinary system. CONCLUSIONS, ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: In this study, we have shown that rat brain concentrations of isoproterenol are only two-fold of that in plasma at equilibrium. If the brain pharmacokinetics are similar in the human brain, it may be difficult to achieve potentially therapeutic levels of this drug safely in humans. Further studies appear warranted to investigate the brain pharmacokinetics in humans with PET using [11C]isoproterenol.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:The UGT1A1*28 polymorphism, although closely linked with CPT-11-related adverse effects, cannot be used alone to guide individualized treatment decisions. However, CPT-11 dosage can be adjusted according to measured SN-38 pharmacokinetics. Our study is designed to investigate whether there is a relationship between SN-38 peak or valley concentrations and efficacy or adverse effects of CPT-11-based chemotherapy. We retrospectively studied 98 patients treated with advanced colorectal cancer in various UGT1A1*28 genotype groups (mainly (TA)6/(TA)6 and (TA)6/(TA)7 genotypes) treated with CPT-11 as first-line chemotherapy in Shanghai. METHODS:One hundred and sixty-four advanced colorectal cancer patients were enrolled. To understand differences in genotype expression, the frequency of UGT1A1*28 thymine-adenine (TA) repeats in TATA box arrangement was assessed by PCR with genomic DNA extracted from peripheral blood. For ninety-eight cases with the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes treated with CPT-11 as first-line chemotherapy, the plasma concentration of SN-38 was detected by HPLC 1.5 and 49 h after CPT-11 infusion. Efficacy and adverse effects were observed subsequently, and the relationship between SN-38 plasma concentration and efficacy or adverse effects within genotype groups, as well as differences in efficacy and adverse effects between (TA)6/(TA)6 and (TA)6/(TA)7 genotypes were analyzed statistically. RESULTS:One hundred and fourteen patients (69.51 %) were identified with the (TA)6/(TA)6 genotype, forty-eight patients (29.27 %) with the (TA)6/(TA)7 genotype, and two patients (1.22 %) with the (TA)7/(TA)7 genotype. The average peak and valley concentrations of SN-38 after CPT-11 infusion and plasma bilirubin average levels before and after CPT-11 treatment in the (TA)6/(TA)7 genotype group were all higher than those in (TA)6/(TA)6 group, and the difference was statistically significant (p = 0.00). Stepwise regression analysis showed that SN-38 peak and valley concentration was correlated with PFS in the (TA)6/(TA)6 genotype. In the (TA)6/(TA)7 group, SN-38 peak concentration was correlated with CPT-11 starting dose and OS, valley concentration correlated with plasma bilirubin levels before CPT-11 treatment, delayed diarrhea, and OS. For the (TA)6/(TA)6 genotype, mPFS of the SN-38 peak concentration >43.2 ng/ml subgroup was significantly longer than that of ≤43.2 ng/ml subgroup (8.0 ± 0.35 vs. 6.5 ± 0.79 months, χ (2) = 17.18, p = 0.00) with a relatively high incidence of Grade I/II° myelosuppression; for the (TA)6/(TA)7 genotype, there was no significant difference in mOS between the SN-38 valley concentration >16.83 ng/ml and ≤16.83 subgroups (17.3 ± 0.45 vs. 18.8 ± 0.50 months, χ (2) = 1.38, p = 0.24), but the former had a higher incidence of Grade III/IV° mucositis and delayed diarrhea. For 2 (TA)7/(TA)7 cases, although 25 % dose reduction of CPT-11, which is calculated according to body surface area, Grade IV° bone marrow suppression and Grade III° delayed diarrhea still occurred after CPT-11 treatment, though both adverse effects resolved and did not recur again after a 50 % dose reduction. CONCLUSION:The (TA)6/(TA)6 genotype and (TA)6/(TA)7 genotype accounted for the most, and (TA)7/(TA)7 genotype only account for a very small portion of advanced colorectal cancer patients in Shanghai. For the (TA)6/(TA)6 genotype, CPT-11 dosage can be increased gradually to improve efficacy for patients with SN-38 peak concentration ≤43.2 ng/ml after CPT-11 infusion; and for (TA)6/(TA)7 genotype patients, CPT-11 dosage may be lowered appropriately to reduce serious adverse effects such as bone marrow suppression and delayed diarrhea without affecting the efficacy for those with SN-38 valley concentration >16.83 ng/ml. For (TA)7/(TA)7 genotype patients, adverse effects should be closely observed after treatment even if CPT-11 dosage has been reduced.

背景与目标：

BACKGROUND & AIMS: :Allopurinol is the drug most widely used to lower the blood concentrations of urate and, therefore, to decrease the number of repeated attacks of gout. Allopurinol is rapidly and extensively metabolised to oxypurinol (oxipurinol), and the hypouricaemic efficacy of allopurinol is due very largely to this metabolite. The pharmacokinetic parameters of allopurinol after oral dosage include oral bioavailability of 79 +/- 20% (mean +/- SD), an elimination half-life (t((1/2))) of 1.2 +/- 0.3 hours, apparent oral clearance (CL/F) of 15.8 +/- 5.2 mL/min/kg and an apparent volume of distribution after oral administration (V(d)/F) of 1.31 +/- 0.41 L/kg. Assuming that 90 mg of oxypurinol is formed from every 100mg of allopurinol, the pharmacokinetic parameters of oxypurinol in subjects with normal renal function are a t((1/2)) of 23.3 +/- 6.0 hours, CL/F of 0.31 +/- 0.07 mL/min/kg, V(d)/F of 0.59 +/- 0.16 L/kg, and renal clearance (CL(R)) relative to creatinine clearance of 0.19 +/- 0.06. Oxypurinol is cleared almost entirely by urinary excretion and, for many years, it has been recommended that the dosage of allopurinol should be reduced in renal impairment. A reduced initial target dosage in renal impairment is still reasonable, but recent data on the toxicity of allopurinol indicate that the dosage may be increased above the present guidelines if the reduction in plasma urate concentrations is inadequate. Measurement of plasma concentrations of oxypurinol in selected patients, particularly those with renal impairment, may help to decrease the risk of toxicity and improve the hypouricaemic response. Monitoring of plasma concentrations of oxypurinol should also help to identify patients with poor adherence. Uricosuric drugs, such as probenecid, have potentially opposing effects on the hypouricaemic efficacy of allopurinol. Their uricosuric effect lowers the plasma concentrations of urate; however, they increase the CL(R) of oxypurinol, thus potentially decreasing the influence of allopurinol. The net effect is an increased degree of hypouricaemia, but the interaction is probably limited to patients with normal renal function or only moderate impairment.

背景与目标： : 别嘌醇是最广泛用于降低尿酸盐血药浓度的药物，因此，减少痛风反复发作的次数。别嘌醇迅速而广泛地代谢为氧嘌呤醇 (oxipurinol)，别嘌醇的低尿酸功效很大程度上归因于这种代谢物。口服后别嘌醇的药代动力学参数包括口服生物利用度79 +/- 20% (平均值 +/- SD)，消除半衰期 (t((1/2) 1.2 +/- 0.3小时，15.8 +/- 5.2 ml/min/kg的表观口服清除率 (CL/F) 和1.31 +/- 0.41 L/kg的口服施用后的表观分布体积 (V(d)/F)。假设每100毫克别嘌醇形成90毫克氧嘌呤醇，肾功能正常的受试者中氧嘌呤醇的药代动力学参数为23.3 +/- 6.0小时的t((1/2))，0.31 +/- 0.07毫升/分钟/千克的CL/F，V(d)/F为0.59 +/- 0.16 L/kg，肾清除率 (CL(R)) 相对于肌酐清除率为0.19 +/- 0.06。氧嘌呤醇几乎完全通过尿排泄清除，多年来，建议在肾功能损害时应减少别嘌醇的剂量。减少肾功能损害的初始目标剂量仍然是合理的，但是有关别嘌醇毒性的最新数据表明，如果血浆尿酸盐浓度的降低不足，则该剂量可能会增加到本指南以上。在选定的患者中，尤其是那些患有肾功能不全的患者中，测量氧尿醇的血浆浓度可能有助于降低毒性风险并改善低尿酸反应。监测氧脲醇的血浆浓度也应有助于识别依从性差的患者。尿尿药物，如丙磺舒，对别嘌醇的低尿酸疗效具有潜在的相反作用。它们的尿尿作用降低了尿酸盐的血浆浓度; 但是，它们会增加氧嘌呤醇的CL(R)，从而可能降低别嘌醇的影响。净效应是低尿酸血症的程度增加，但相互作用可能仅限于肾功能正常或仅中度受损的患者。

BACKGROUND & AIMS: AIM:To investigate the pharmacokinetics and clinical efficacy of intravenous (i.v.) and intramuscular (i.m.) lorazepam (LZP) in children with severe malaria and convulsions. METHODS:Twenty-six children with severe malaria and convulsions lasting > or =5 min were studied. Fifteen children were given a single dose (0.1 mg kg(-1)) of i.v. LZP and 11 received a similar i.m. dose. Blood samples were collected over 72 h for determination of plasma LZP concentrations. Plasma LZP concentration-time data were fitted using compartmental models. RESULTS:Median [95% confidence interval (CI)] LZP concentrations of 65.1 ng ml(-1) (50.2, 107.0) and 41.4 ng ml(-1) (22.0, 103.0) were attained within median (95% CI) times of 30 min (10, 40) and 25 min (20, 60) following i.v. and i.m. administration, respectively. Concentrations were maintained above the reported therapeutic concentration (30 ng ml(-1)) for at least 8 h after dosing via either route. The relative bioavailability of i.m. LZP was 89%. A single dose of LZP was effective for rapid termination of convulsions in all children and prevention of seizure recurrence for >72 h in 11 of 15 children (73%, i.v.) and 10 of 11 children (91%, i.m), without any clinically apparent respiratory depression or hypotension. Three children (12%) died. CONCLUSION:Administration of LZP (0.1 mg kg(-1)) resulted in rapid achievement of plasma LZP concentrations within the reported effective therapeutic range without significant cardiorespiratory effects. I.m administration of LZP may be more practical in rural healthcare facilities in Africa, where venous access may not be feasible.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Immunoglobulin products are widely used across multiple therapeutic areas such as immunodeficiency syndromes, infection and autoimmune diseases. The pharmacokinetics (PK) of immunoglobulins are well characterized in adults, but very little is known about the PK of immunoglobulins in neonates and infants (<2 years of age). OBJECTIVE:The objectives of the present study were: (1) characterize the PK of immunoglobulin intravenous preparation using model-independent (non-compartmental analysis), and (2) develop and evaluate a population PK model with extensive blood samples (8 blood samples) and sparse blood samples (2-3 blood samples). METHOD:Immunoglobulin G (IgG) concentration versus time data from very low birth weight neonates (n = 20) following intravenous administration were analyzed using nonlinear mixed effect modeling and non-compartmental approaches. Population pharmacokinetic models were developed from extensive and sparse sampling schemes. Models were evaluated based on the difference in objective function, goodness-of-fit plots and simulation based visual predictive check analysis. RESULTS:A non-compartmental analysis of IgG from neonates (bodyweight range 0.78-1.38 kg) indicated an average clearance of 3.0 ± 2.1 mL/day and volume of distribution at steady state 68 ± 25 mL. The population pharmacokinetic model from extensive sampling adequately described concentration- time data with mean clearance (2.7 mL/day), volume of central compartment (8.7 mL) and peripheral compartment (60 mL). The clearance and volume of distribution estimates using sparse sampling model (1 pre-and 2 post-dose blood samples) were comparable with extensive sampling. CONCLUSION:Our study provides important bridging data in scaling PK and dosing of immunoglobulins across a wide age range.

背景与目标：

BACKGROUND & AIMS: :The disposition of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3-a]pyridine (1), a potent and selective inhibitor of mitogen activated protein (MAP) kinase p38alpha, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 1 demonstrated generally favorable pharmacokinetic properties in all species examined. Following intravenous (i.v.) administration, 1 exhibited low volumes of distribution at steady state (Vd(ss)) ranging from 0.4-1.3 l/kg (2.4-26 l/m(2)) in the rat, dog and monkey. Systemic plasma clearance was low in cynomolgus monkeys (6.00 ml/min/kg, 72.0 ml/min/m(2)) and Sprague-Dawley rats (7.65+/-1.08 ml/min/kg, 45.9+/-6.48 ml/min/m(2) in male rats and 3.15+/-0.27 ml/min/kg, 18.9+/-1.62 ml/min/m(2) in female rats) and moderate in beagle dogs (12.3+/-5.1 ml/min/kg, 246+/-102 ml/min/m(2)) resulting in plasma half-lives ranging from 1 to 5 h in preclinical species. Moderate to high bioavailability of 1 was observed in rats (30-65%), dogs (87%) and monkeys (40%) after oral (p.o.) dosing consistent with the in vitro absorption profile of 1 in the Caco-2 permeability assay. In rats, the oral pharmacokinetics were dose dependent over the dose range studied (5, 50 and 100 mg/kg). The principal route of clearance of 1 in rat, dog, monkey and human liver microsomes and in vivo in preclinical species involved oxidative metabolism mediated by cytochrome P450 enzymes. The major metabolic fate of 1 in preclinical species and humans involved hydroxylation on the isopropyl group to yield the tertiary alcohol metabolite 2. In human liver microsomes, this transformation was catalysed by CYP3A4 as judged from reaction phenotyping analysis using isozyme-specific inhibitors and recombinant CYP enzymes. Metabolite 2 was also shown to possess inhibitory potency against p38alpha in a variety of in vitro assays. 1 as well as the active metabolite 2 were moderately to highly bound to plasma proteins (f(u) approximately 0.1-0.33) in rat, mouse, dog, monkey and human. 1 as well as the active metabolite 2 did not exhibit competitive inhibition of the five major cytochrome P450 enzymes namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC(50)>50 microM). Overall, these results indicate that the absorption, distribution, metabolism and excretion (ADME) profile of 1 is relatively consistent across preclinical species and predict potentially favorable pharmacokinetic properties in humans, supporting its selection for toxicity/safety assessment studies and possible investigations in humans as an anti-inflammatory agent.

背景与目标： : 6-(4-(2,5-二氟苯基) oxazol-5-yl)-3-异丙基-[1,2，4]-三唑并 [4,3-a] 吡啶 (1) 的处置，这是一种有效且选择性的丝裂原活化蛋白 (MAP) 激酶p38alpha抑制剂，在几种动物物种中被描述为支持其临床前安全性研究和潜在临床开发的选择。1在所有被检查的物种中表现出普遍有利的药代动力学特性。静脉注射 (静脉注射) 给药后，1在大鼠，狗和猴子中表现出0.4-1.3 l/kg (2.4-26 l/m(2)) 的稳态下低分布量 (Vd(ss))。食蟹猴的全身血浆清除率低 (6.00毫升/min/kg，72.0毫升/min/m(2)) 和Sprague-Dawley大鼠 (7.65 +/-1.08毫升/min/kg，45.9 +/-6.48毫升/min/m(2) 在雄性大鼠和3.15 +/-0.27毫升/min/kg，18.9 +/-1.62毫升/min/m (雌性大鼠2) 和比格犬中等 (12.3 +/-5.1毫升/min/kg，246 +/-102毫升/min/m(2)) 导致临床前物种的血浆半衰期为1至5 h。在大鼠 (30-65%) 中观察到中度至高生物利用度1，狗 (87%) 和猴子 (40%) 口服 (p.o.) 给药后与Caco-2通透性测定中1的体外吸收曲线一致。在大鼠中，口服药代动力学在研究的剂量范围内是剂量依赖性的 (5，50和100 mg/kg)。1在大鼠，狗，猴子和人类肝微粒体以及临床前物种的体内涉及细胞色素P450酶介导的氧化代谢。1在临床前物种和人类中的主要代谢命运涉及异丙基上的羟基化以产生三级醇代谢物2。在人类肝微粒体中，根据使用同工酶特异性抑制剂和重组CYP酶的反应表型分析判断，这种转化是由CYP3A4催化的。在各种体外测定中，代谢物2也显示出对p38alpha的抑制能力。1以及活性代谢物2与血浆蛋白中度至高度结合 (f(u) 大约0.1-0.33) 在大鼠中，小鼠，狗，猴子和人。1以及活性代谢物2没有表现出对五种主要细胞色素P450酶的竞争性抑制，即CYP1A2，2C9，2C19，2D6和3A4 (IC(50)>50微米)。总的来说，这些结果表明吸收，分布，1的代谢和排泄 (ADME) 概况在临床前物种中相对一致，并预测了人类潜在的有利药代动力学特性，支持其选择毒性/安全性评估研究以及在人类中作为抗炎剂的可能研究。

BACKGROUND & AIMS: :This study included 24 healthy volunteers who received a single 37.5 mg oral dose of tramadol. We analyzed 18 polymorphisms within CYP2D6, CYP2B6, CYP3A, COMT, ABCB1, SLC22A1 and OPRM1 genes by quantitative PCR, to study whether these polymorphisms affect its pharmacokinetics, pharmacodynamics and safety. CYP2D6 intermediate metabolizers (n = 6) showed higher tramadol plasma concentrations and lower clearance compared with normal and ultrarapid metabolizers. CYP2B6 G516T T/T (n = 2) genotype was also associated to higher tramadol plasma levels. No other polymorphism affected tramadol pharmacokinetics. Three volunteers experienced a prolonged QTc not associated with the genetic variants studied or altered phamacokinetic parameters. The correlation of CYP2B6 genotype with higher tramadol concentrations is remarkable since its influence on its elimination is also relevant and has been less studied to date. However, given our small sample size, it is important to interpret our results with caution.

背景与目标： : 这项研究包括24名健康志愿者，他们接受了单次37.5毫克的曲马多口服剂量。我们通过定量PCR分析了CYP2D6，CYP2B6，CYP3A，COMT，ABCB1，SLC22A1和OPRM1基因内的18个多态性，以研究这些多态性是否影响其药代动力学，药效学和安全性。CYP2D6中间代谢者 (n = 6) 显示出较高的曲马多血浆浓度和较低的清除率与正常和超类代谢者相比。CYP2B6 G516T T/T (n = 2) 基因型也与较高的曲马多血浆水平相关。没有其他多态性影响曲马多的药代动力学。三名志愿者经历了长时间的QTc，与所研究的遗传变异或遗传动力学参数的改变无关。CYP2B6基因型与较高曲马多浓度的相关性是显着的，因为它对其消除的影响也是相关的，迄今为止研究较少。但是，鉴于我们的样本量较小，因此谨慎解释我们的结果很重要。

BACKGROUND & AIMS: OBJECTIVE:To study the effect of continuous veno-venous hemofiltration (CVVHF) on the pharmacokinetics of levofloxacin in critically ill patients with acute renal failure. DESIGN:Open-label study. SETTING:Anesthesiology ICU, University Hospital of Regensburg. PATIENTS:Six critically ill patients treated with CVVHF because of acute renal failure needing antimicrobial therapy. INTERVENTIONS:Levofloxacin i.v. 250 mg qd with a starting dose of 500 mg. CVVHF with the following characteristics: hemofilter AN69 hollow fibers of 0.90 m2 area, blood flow 150 ml/min, ultrafiltrate flow 1.3 l/h, filtrate substitution in post-dilution mode. MEASUREMENTS AND RESULTS:The plasma pharmacokinetics and clearance of levofloxacin by hemofiltration were established on day 1 and day 4-6 of treatment. Levofloxacin was determined by high-performance liquid chromatography (HPLC). Mean (range) peak plasma concentrations after levofloxacin 500 mg single dose (s.d.) and 250 mg multiple dose (m.d.) were 6.4 (2.7-9.4) and 8.2 (4.7-10.3) mg/l, trough levels 2.7 (1.4-5.0) and 2.9 (1.7-3.9) mg/l, half-life 28 (19-38) and 22 (17-31) h, volume of distribution 1.2 (0.72-1.6) l/kg and 0.91 (0.52-2.0) l/kg, respectively. The mean sieving coefficient was 0.96 (0.79-1.09), mean total clearance 47 (20-89) ml/min, and mean clearance by hemofiltration 21 (13-27) ml/min, respectively. CONCLUSIONS:A dosage schedule of levofloxacin 250 mg qd with a 500 mg loading dose seems appropriate for anuric patients during CVVHF. Sufficiently high steady-state concentrations of levofloxacin were achieved after the first dose. Undesired accumulation of levofloxacin was not observed.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:To testify that the asialoorosomucoid (ASOR) prepared by us has liver-targeting specificity and to investigate its pharmacokinetic characteristics. METHODS:The distribution of 125I-ASOR in vivo was determined by single photon emission computed tomography (SPECT) and immunohistochemical technique after 125I-ASOR was injected into Sprague-Dawley (S-D) rats through their caudal veins. In vitro, different doses of pEGFP-N1 plasmid were transfected into both HepG2 cells and HT1080 cells with the use of ASOR-poly-L-lysine. At 24 and 48 h after transfection, the expression of green fluorescent protein (GFP) was determined under fluorescent microscope. Pharmacokinetic parameters were calculated according to two-compartment open system model with first-order kinetics. RESULTS:SPECT images showed that 125I-ASOR was located only in liver/stomach and root of caudal vein/bladder at 10 min after injection. The 125I-ASOR radioactivities of organs taken out from S-D rats were different at different times, and about 63% of 125I-ASOR was located in the liver at 10 min after injection. At 30 min after injection a peak of radioactivity was seen in stomach. The times of these two radioactivity peaks were different. Immunohistochemical study of liver frozen sections showed that ASOR was combined mainly with hepatocyte membrane, especially in areas with rich blood flow. In vitro study showed that ASOR targeted specifically cells with asialoglycoprotein receptor (ASGr). GFP expression was detected in HepG2 cells but not in HT1080 cells. Furthermore, the more quantity of pEGFP-N1 transfected and the longer expression time, the higher GFP expression level was in HepG2 cells. The 125I-ASOR pharmacokinetics equation for liver was Ct=662216e-3.362t+8896e-2343t. 125I-ASOR was excreted from liver slowly after an initial rapid decrease. The pharmacokinetic equation for stomach was Ct=-114815e-1.7t+1148153e-15t and the half-life of 125I-ASOR in stomach was 4.62 h. CONCLUSIONS:ASOR prepared by us could be an efficient gene transfer vector, ASOR was distributed mainly in the liver and stomach and had high targeting specificity to hepatocytes or hepatic originating cells.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:This study was undertaken to study the pharmacokinetics of intravenously administered amoxicillin in pregnant women with preterm premature rupture of the membranes (PPROM). STUDY DESIGN:Healthy women with PPROM were recruited and treated with amoxicillin (2 g initially and 1 g subsequently). Blood samples were obtained from the opposite arm and concentrations determined with the use of high-pressure liquid chromatography. Nonlinear mixed-effects modeling was performed in nonlinear mixed effect (population) modeling. RESULTS:The pharmacokinetics of 17 patients was described by a 3-compartment model. Clearance and volume of distribution at steady state were 22.8 L/h and 21.4 L/h, respectively, similar to values in nonpregnant individuals. There was little variability between patients. No relationship was observed between values of individual pharmacokinetic parameters and various covariates. CONCLUSION:The pharmacokinetics of amoxicillin in pregnant patients with PPROM similar to nonpregnant individuals. Given the small interindividual variability in pharmacokinetics, no dose adjustments are required to account for differences between subjects under normal circumstances.

背景与目标：