氯胺酮对丙泊酚药动学与药效学的影响研究

目的:研究氯胺酮对丙泊酚静脉麻醉后药动学、药效学的影响。方法:24例门诊无痛人流术患者随机分为2.5mg·kg-1丙泊酚静脉麻醉组(A组,n=8)、复合0.25mg·kg-1氯胺酮组(B组,n=8)及复合0.75mg·kg-1氯胺酮组(C组,n=8)。分别在停止注射丙泊酚后0、2、4、6、8、10、15、30、45min与1、2、3h及唤醒、清醒时采集未注药侧肘静脉血,用高效液相色谱法测定单次给药后各时点丙泊酚血药浓度,并由3p97软件处理计算出药动学参数,同时监测相应时间点收缩压(SBP)、舒张压(DBP)、心率(HR)、血氧饱和度(SpO2)。结果:与A组比较,B、C组的t1/2α、Vd呈减少趋势(A、C组比较:P<0.05);B、C组的K12、CL呈增加趋势(A、C组比较:P<0.05)。3组间t1/2β、K21、K10差异无统计学意义。停止注射丙泊酚后1～4min血压、HR、SpO2变化明显,SBP、DBPA、C组比较:P<0.05或B、C组比较:P<0.05;HRA、C组比较:P<0.05;SpO2A、C组比较:P<0.05。结论:单次静脉注射氯胺酮0.75mg·kg-1可促进丙泊酚的分布或再分布,而氯胺酮0.25mg·kg-1对丙泊酚分布或再分布无明显影响。2.5mg·kg-1丙泊酚复合0.25mg·kg-1氯胺酮用于无痛人流术安全、有效。     

Liposomal Methylprednisolone in Rats: Dose-Proportionality and Chronic-Dose Pharmacokinetics/Pharmacodynamics

Purpose. Methylprednisolone (MPL) encapsulated in liposomes (L-MPL) targets the immune system and enhances immunosuppressive activity of the steroid. We performed dose-dependent and chronic dose studies of L-MPL versus MPL. Methods. Male Lewis rats received 10 mg/kg IV bolus doses of L-MPL (Solu-Medrol). Plasma samples were obtained over an 8 day period and MPL concentrations were assayed by HPLC. Immunosuppressive effects were measured as inhibition of ex vivo splenocyte proliferation induced with PHA. Results. Drug concentrations declined in a similar manner over the first few hours following MPL or L-MPL. Free MPL was cleared from plasma by 6 hr, while the same dose of L-MPL resulted in persistance over an 8-day period. Dose-dependent changes in pharmacokinetic parameters were observed for both free and liposomal drug. Increasing the dose from 2 to 10 mg/kg led to increased clearance from 5.9 to 10.5 (MPL) and from 1.8 to 2.3 L/hr/kg (L-MPL). Blastogenesis was suppressed over 5 days with return to the baseline at day 8 (L-MPL); free MPL produced immunosuppression only over 10 hr. Multiple 2 mg/kg IV doses of L-MPL versus MPL twice a week produce plasma drug profiles similar to those obtained after single doses, indicating that neither free nor liposomal steroid accumulates in tissues. Liposomes without drug simultaneously administered with MPL caused partial prolongation of plasma steroid half-life (8.4 hr). Conclusions. These studies clarify factors causing prolonged drug persistence and immunosuppression with L-MPL. Nonlinear disposition, irregular pharmacokinetics, and secondary effects of the liposomes are complicating factors in use of L-MPL.     

Cocaine Pharmacokinetics/ Pharmacodynamics in Awake Freely Moving Rats

Pharmaceutical Research -     

Circadian Changes in the Pharmacokinetics and Pharmacodynamics of Azosemide in Rats

The circadian changes in the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous and oral administration of the drug (10 mg kg^?1) to rats at 1000 or 2200 h. After intravenous administration of azosemide the percentage of the dose excreted in 8-h urine as unchanged azosemide was significantly higher in the 1000 h group than in the 2200 h group (41.7 compared with 28.9%) and this resulted in a significant increase in 8-h urine output (84.7 compared with 36.6 mL/100 g). After intravenous administration the time-averaged renal clearance (CL_R) of azosemide was significantly faster (2.86 compared with 1.76 mL min^?1 kg^?1) and urinary excretion of sodium (46.4 compared with 25.9 mmol/100 g) and chloride (35.6 compared with 18.8 mmol/100 g) increased significantly in the 1000 h group. However, after oral administration, the percentages of oral dose of azosemide excreted in 8-h urine as unchanged azosemide were significantly higher (1.88 compared with 0.67%) and the CL_R of azosemide was significantly faster (3.64 compared with 0.79 mL min^?1 kg^?1) in the 2200 h group. This could be at least partly because of increased absorption of azosemide from the gastrointestinal tract in the 2200 h group; the percentages of oral dose of azosemide recovered from the gastrointestinal tract in 8 h as unchanged azosemide was significantly smaller (5.7 compared with 13.2%) in the 2200 h group. The pharmacodynamic parameters of azosemide were not significantly different after oral administration of the drug to both groups of rats. If these data could be extrapolated to man, the intravenous dose of azosemide could be modified on the basis of circadian time.     

Facilitation of Pulmonary Insulin Absorption by H-MAP: Pharmacokinetics and Pharmacodynamics in Rats

Purpose. Several low molecular weight amino acids have previously been reported to enable the oral delivery of proteins. In the present studies, the effect of H-MAP (hydroxy methyl amino propionic acid) on the pharmacokinetics (PK) and pharmacodynamics (PD) of porcine insulin delivered to the lungs of rats by spray-instillation (SI) has been determined. Methods. Aliquots (100 l) of increasing doses of porcine insulin alone (0.26, 1.3, 2.6, 13, and 26 U/kg) or combined with increasing doses of H-MAP (5, 10, 16, and 25 mg/kg), at pH 7.2-7.6 were administered intratracheally to fasted anesthetized rats using a micro spray-instillator. Blood samples were collected from the jugular vein at specified intervals and the plasma concentrations of insulin and glucose were determined. The PK and PD of porcine insulin alone following subcutaneous (SC) administration of increasing doses were also determined. Results. The PK of insulin administered either by SI to the lungs or SC injection were absorption rate dependent, resulting in post-peak half-lives 10 to 25-fold greater than the reported intravenous elimination half-life (3 min). The relative bioavailability (F') of insulin administered alone by SI varied from 23.8 to 80% for the lowest and highest insulin dose, respectively. Co-administration of H-MAP and insulin to the lungs significantly changed the PK and PD of insulin in a dose dependent fashion. Maximum PK and PD responses were obtained at an H-MAP dose of 16 mg/kg and an insulin dose of 1.3 U/kg. At this combination, the relative bioavailability of insulin was increased more than 2.5 fold, maximum concentration (C_max) increased 2-fold and the minimum plasma glucose concentration (%MPGC) was reduced more than 2-fold with respect to same dose of insulin alone. A greater total reduction in plasma glucose (%TRPG_0t) was achieved for H-MAP/insulin combination (66 ± 5 %) compared to insulin alone (47 ± 10 %). Conclusion. H-MAP has potential for increasing the pulmonary bioavailability of insulin administered through the lungs.     

Influence of Different Fat Emulsion-Based Intravenous Formulations on the Pharmacokinetics and Pharmacodynamics of Propofol

Purpose. The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint. Methods. Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%^®-like fat emulsion (Diprivan-10^®, D) or as a 1%- or 6% emulsion in Lipofundin^® MCT/LCT-10% (Pl% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC. Results. Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compart-mental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (V_d,ss) and terminal half-life (t_{1/2, 2}) were 107 ± 4 ml/min/kg, 1.38 ± 0.06 l/kg and 16 ± 1 min, respectively (mean ± S.E., n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 ± 11 ml/min/kg, 5.19 ± 0.41 l/kg and 45 ± 3 min, respectively (mean±S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both V_d,ss and t_{1/2, 2} (p < 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t,_{1/2, keo}) was observed compared to the other propofol formulations (p<0.05). Conclusions. The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.     

Effects of Sho-saiko-to on the Pharmacokinetics and Pharmacodynamics of Tolbutamide in Rats

Although Sho-saiko-to (Xiao Chai Hu Tang), a major Chinese traditional medicine, is frequently prescribed with other synthetic or biotechnological drugs for the treatment of various chronic diseases, there is a dearth of information about interactions between sho-saiko-to and co-administered drugs. This paper reports the effects of Sho-saiko-to on the pharmacokinetics and glucose responses of a sulphonylurea hypoglycaemic agent, tolbutamide, after their oral administration in rats. After oral administration of tolbutamide (50 mg kg^?1) with or without Sho-saiko-to extract powder (300 mg kg^?1) to male Sprague-Dawley rats cannulated in the jugular vein, plasma tolbutamide and glucose levels were periodically measured. Co-administration of Sho-saiko-to tended to elevate the plasma tolbutamide concentration in the absorption phase. A two-compartment lag-time model was found to describe the plasma tolbutamide concentration-time data. The maximum concentration of tolbutamide was significantly increased and time to reach the maximum concentration was reduced to about 70% by co-administration with Sho-saiko-to. There was no significant change in area under the curve or in the elimination half-life of tolbutamide. The extent of the lowering effect of tolbutamide on plasma glucose levels was increased up to 0.75 h and decreased after 5 h after co-administration of Sho-saiko-to. In conclusion, these studies suggest that sho-saiko-to slightly hastens the gastrointestinal absorption of tolbutamide. Furthermore, it is considered that elevation of the gastrointestinal absorption rate by Sho-saiko-to might potentiate the hypoglycaemic effect of this sulphonylurea in the early period after oral administration.     

阿奇霉素对大鼠灌服华法林的药效学和药动学的影响

目的：研究抗生索阿奇霉素对大鼠灌服华法林的药效学指标凝血酶原时间（PT）和国际标准化比值（INR）以及药动学指标血药浓度的影响。方法：将SD大鼠随机分成两组：单用华法林组（A组）和华法林＋阿奇霉素合用组（B组）,每组大鼠灌胃给予华法林0．2mg·kg^-1,每日1次,连续613,其中B组大鼠在第6日最后1次灌胃给予华法林后立即腹腔注射阿奇霉素80mg·kg^-1,且开始计时,分别于0．25、0．5、1．5、2．5、3．5、5、7、10、13小时采血,测定PT,计算INR。并建立HPLC法,测定华法林血药浓度。结果：从5小时开始,B组大鼠的胛值较A组显著增大（P〈0．05）,INR值最高可达7．5;B组大鼠的华法林药动学参数咒。较A组显著延长（P〈0．01）,其他药动学参数无显著性差异;两组大鼠的INR-C曲线都呈逆时针走向,且B组的逆时针效应更甚。结论：阿奇霉素与华法林合用可发生药效学和药动学相互作用,增强华法林的抗凝作用,增加用药者的出血风险,故临床上两药合用时应密切监测用药者的INR值,避免严重不良反应的发生。     

Biopharmaceutics: Drug Metabolism and Pharmacokinetics: Circadian Variations in the Pharmacokinetics of Pentoxifylline in Man

Optimization of therapy by chronopharmacology requires knowledge of rhythmic manifestations of disease activity and chronopharmacokinetic data of the drugs prescribed. Rhythmic functioning of the cardiovascular system in healthy and diseased subjects is manifested as circadian rhythms in blood pressure, cardiac output, heart rate, etc. The disposition of several cardiovascular drugs in man has been reported to be time-dependent. This study reports the effect of time of administration on the disposition of pentoxifylline. Twelve healthy volunteers were treated with 400 mg pentoxifylline orally at 0100, 0700, 1300 and 1900 h in a randomized crossover Latin-square design with a wash-out period of one week. Serum samples were analysed for unchanged pentoxifylline by HPLC. Pharmacokinetic parameters were calculated using a model-independent method. The mean values of various pharmacokinetic parameters after drug treatment at these times were, respectively: maximum plasma concentration (C_max) 485 ± 174, 646 ± 175, 735 ± 271 and 781±217 ng mL^?1; time to reach the maximum plasma concentration (T_max) 1.90±0.39, 1.66±0.4, 1.31 ± 0.41 and 1.32 ± 0.44 h, mean residence time (MRT) 3.8 ± 0.8, 2.9 ± 0.5, 2.9 ± 0.4 and 2.7 ± 0.3 h, elimination half-life (t1/2) 1.93 ± 0.86, 1.23 ± 0.3, 1.39 ± 0.3 and 1.23 ± 0.18 h and volume of distribution at steady state (Vd_ss/f) 11991 ± 4862, 8823 ± 3484, 8275 ± 2357 and 7063 ± 1950 mL kg^?1. The mean C_max value was significantly (P < 0.05) lower after drug administration at 0100 h than after other time-points whereas mean T_max, MRT, Vd_ss/f and t1/2 values were significantly (P < 0.05) higher. These variations might be because of time-dependent changes in absorption and biliary excretion of pentoxifylline and should be borne in mind when designing sustained action dosage forms for the drug.     

《生物药剂学与药物动力学》教材中药物动力学部分编写的建议

完善生物药剂学与药物动力学的教材编写,积累长期的教学经验,结合药物动力学的相关文献报道和应用实践,提出提高教材编写质量的改进建议。     

Pharmacokinetics and Pharmacodynamics of Ibrexafungerp

On 2 June, 2021, the US Food and Drug Administration approved ibrexafungerp (formerly MK-3118 and SCY-078) for the treatment of vulvovaginal candidiasis, also known as vaginal yeast infection. Ibrexafungerp is the first drug approved in a novel antifungal class in more than two decades, and the Food and Drug Administration’s decision was based on positive results from two pivotal phase III studies in which oral ibrexafungerp proved both safe and effective in patients with vulvovaginal candidiasis. The decision was also based on substantial preclinical and clinical work in both the pharmacokinetics and pharmacodynamics of ibrexafungerp. This paper reviews that research and looks ahead to explore how this novel antifungal agent may be used in the future to address the expanding problem of drug-resistant mycotic infections.     

Pharmacokinetics and Pharmacodynamics of Nitrendipine

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Volterra Series in Pharmacokinetics and Pharmacodynamics

Nonparametric black-box modeling has a long successful history of applications in pharmacokinetics (PK) (notably in deconvolution), but is rarely used in pharmacodynamics (PD). The main reason is associated with the fact that PK systems are often linear in respect to drug inputs, while the reverse is true for many PK/PD systems. In the PK/PD field existing non-parametric methods can deal with linear systems, but they cannot describe non-linear systems. Our purpose is to describe a novel implementation of a general nonparametric model which can represent non-linear systems, and in particular non-linear PK/PD systems, The model is based on a Volterra series, which is an integral series expansion of the response of a system in terms of its kernels and the inputs to the system. In PK we are familiar with the first term of the Volterra series, the convolution of the first kernel of the system (the so-called PK disposition function) with drug input rates. The main advantages of higher order Volterra representations is that they are general representations and can be used to describe and predict the response of an arbitrary (PK/ PD) system without any prior knowledge on the structure of the system. The main problem of the representation is that in a non-parametric representation of the kernels the number of parameters to be estimated grows geometrically with the order of the kernel. We developed a method to estimate the kernels in a Volterra-series which overcomes this problem. The method (i) is fully non-parametric (the kernels are represented using multivariate splines), (ii) is maximum-likelihood based, (iii) is adaptive (the order of the series and the dimensionality of each kernel is selected by the method), and (iv) allows for non-equispaced observations (thus allowing a reduction of the number of parameters in the representation, and the analysis of, e.g., PK/PD observations). The method is based on an adaptation of Friedmans's Multivariate Adaptive Regression Spline method. Examples demonstrate the possible application of the approach to the analysis of different PK/PD systems.     

Novel Lipid and Preservative-free Propofol Formulation: Properties and Pharmacodynamics

Purpose

Propofol is a water-insoluble intravenous anesthetic agent that is actually formulated as a water-in-oil emulsion with known drawbacks such as pain on injection, microorganism growth support and stability. We report on the properties of formulations of propofol in poly (N-vinyl-2-pyrrolidone)-block-poly(d,l-lactide), PVP–PLA, polymeric micelles (Propofol-PM).

Methods

Microbial growth in these formulations was evaluated with Pseudomonas aeruginosa (ATCC 9027), Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 25922) and Candida albicans (ATCC 10231). Sleep-recovery studies in female Sprague–Dawley rats, at a dose of 10mg/kg were performed to compare pharmacodynamic profiles of the new Propofol-PM formulations with those of Diprivan®, a commercially available lipid based propofol formulation.

Results

Growth of microorganisms was not supported in the Propofol-PM formulations tested. No significant differences in times to unconsciousness, awakening, recovery of righting reflex and full recovery were observed between Propofol-PM formulations and Diprivan®.

Conclusions

Propofol loaded in PVP–PLA micelles (Propofol-PM) is not significantly different in terms of pharmacodynamic but demonstrates no microorganism growth support and improved stability that opens up the door to pain on injection reduction strategy.

     

Pharmacokinetics and Pharmacodynamics of Pentazocine in Children

Pharmacokinetics and ventilatory effects of a single intravenous dose of 0.5 mg/kg of pentazocine were studied in ten children aged 4 to 8 years after ophthalmic surgery. Elimination half-life (mean ± S.D.) was 3.0×1.5 hr and clearance 21.8×5.9 ml/min./kg. The values for V_c, V_ss and V_β were 0.73×0.21, 4.0×1.2 and 5.3×2.1 1/kg, respectively. The pharmacokinetic parameters were similar to those of adults. After administration of pentazocine decrease in ventilatory rate and oxygen saturation and increase in end-tidal carbon dioxide were relatively fast and steep. Oxygen saturation of four patients decreased below 90% and in one patient the decrease did not recover instantly and additional oxygen was given for 2 min. No patient needed assisted ventilation. Only clinically insignificant changes in heart rate and mean arterial pressure were observed. The duration of analgesia was 164 × 59 min. No serious side-effects appeared.     

Pharmacokinetics and Pharmacodynamics of an Investigational Antipsychotic Agent,CI-1007, in Rats and Monkeys

Purpose. To study the pharmacokinetics (PK) and pharmacodynamics (PD) of an investigational antipsychotic agent, CI-1007, in rats and monkeys. Methods. CI-1007 and a pharmacologically active metabolite, PD 147693 (Ml), were evaluated in animal antipsychotic tests (inhibition of dopamine neuron firing and spontaneous locomotor activity in rats, and inhibition of continuous avoidance in monkeys). Plasma concentrations of CI-1007 and Ml were determined using validated HPLC assays. Log-linear and link models were used for PK/PD analysis. Results. CI-1007 and Ml have shown similar effects on dopamine neuron firing (2.5 mg/kg i.p.), and produced dose-related effects on spontaneous locomotor activity in rats (0.3–30 mg/kg, p.o.) and on continuous avoidance in monkeys (0.6–1.2 mg/kg p.o.). After pharmacologically active CI-1007 doses, mean plasma CI-1007 C_max increased from 19 to 200 ng/ml in Sprague-Dawley rats at doses of 3–30 mg/ kg, and from 8.1 to 34 ng/ml in squirrel monkeys at doses of 0.6–1.2 mg/kg, but corresponding plasma M1 C_max values were near or below the limit of quantitation (5 ng/ml). CI-1007 EC50 was 31.1 ng/ml in rats, calculated from a log-linear regression. In monkeys, CI-1007 EC_e50, , and K_eo at 0.6 and 1.2 mg/kg were 4.8 and 4.5 ng/ml, 1.9 and 2.0, and 0.47 and 0.48 hr^–1, respectively, calculated by the link model. Conclusions. CI-1007 has shown dose-related pharmacokinetics and pharmacodynamics in rats and monkeys. Although Ml produces anti-psychotic-like effects similar to CI-1007, the contribution of Ml to the activity of the parent drug may not be significant in rats and monkeys as based on plasma levels. CI-1007 plasma concentration correlates log-linearly with inhibition effect from the rat locomotor study. The counter-clockwise hysteresis relationship of CI-1007 plasma concentration and inhibition effect from the monkey avoidance test was described by a link model, and the resulting C_e (concentration in effect compartment) versus effect profile exhibits a sigmoidal curve.