泊沙康唑药动学-药效学及其治疗药物监测研究进展

泊沙康唑为新一代三唑类广谱抗真菌药,临床主要用于侵袭性曲霉菌病、念珠菌病的预防和难治性口咽念珠菌病的治疗,具有抗菌 活性高、耐受性好、不良反应少等特点,但其口服后生物利用度具有较大的个体差异。综述泊沙康唑混悬液的药动学影响因素、不同患者 人群的药动学特征以及群体药动学特征、药动学 / 药效学特性、治疗药物监测对临床疗效和不良反应的重要影响,以指导临床个体化用药, 提高用药的有效性和安全性。     

生物技术药物药代动力学研究的方法学和实验设计

生物技术药物由于自身具有的特点 ,使得其在体内的药代动力学机制比传统药物更为复杂。近年来 ,对于这类药物在体内的代谢机制的研究日趋增加 ,研究方法也日趋成熟。概述了生物技术药物的药代动力学研究方法以及实验设计的特点。     

The interplay of non-specific binding,target-mediated clearance and FcRn interactions on the pharmacokinetics of humanized antibodies

The application of protein engineering technologies toward successfully improving antibody pharmacokinetics has been challenging due to the multiplicity of biochemical factors that influence monoclonal antibody (mAb) disposition in vivo. Physiological factors including interactions with the neonatal Fc receptor (FcRn) and specific antigen binding properties of mAbs, along with biophysical properties of the mAbs themselves play a critical role. It has become evident that applying an integrated approach to understand the relative contribution of these factors is critical to rationally guide and apply engineering strategies to optimize mAb pharmacokinetics. The study presented here evaluated the influence of unintended non-specific interactions on the disposition of mAbs whose clearance rates are governed predominantly by either non-specific (FcRn) or target-mediated processes. The pharmacokinetics of 8 mAbs representing a diverse range of these properties was evaluated in cynomolgus monkeys. Results revealed complementarity-determining region (CDR) charge patch engineering to decrease charge-related non-specific binding can have a significant impact on improving the clearance. In contrast, the influence of enhanced in vitro FcRn binding was mixed, and related to both the strength of charge interaction and the general mechanism predominant in governing the clearance of the particular mAb. Overall, improved pharmacokinetics through enhanced FcRn interactions were apparent for a CDR charge-patch normalized mAb which was affected by non-specific clearance. The findings in this report are an important demonstration that mAb pharmacokinetics requires optimization on a case-by-case basis to improve the design of molecules with increased therapeutic application.     

The interplay of non-specific binding,target-mediated clearance and FcRn interactions on the pharmacokinetics of humanized antibodies

The application of protein engineering technologies toward successfully improving antibody pharmacokinetics has been challenging due to the multiplicity of biochemical factors that influence monoclonal antibody (mAb) disposition in vivo. Physiological factors including interactions with the neonatal Fc receptor (FcRn) and specific antigen binding properties of mAbs, along with biophysical properties of the mAbs themselves play a critical role. It has become evident that applying an integrated approach to understand the relative contribution of these factors is critical to rationally guide and apply engineering strategies to optimize mAb pharmacokinetics. The study presented here evaluated the influence of unintended non-specific interactions on the disposition of mAbs whose clearance rates are governed predominantly by either non-specific (FcRn) or target-mediated processes. The pharmacokinetics of 8 mAbs representing a diverse range of these properties was evaluated in cynomolgus monkeys. Results revealed complementarity-determining region (CDR) charge patch engineering to decrease charge-related non-specific binding can have a significant impact on improving the clearance. In contrast, the influence of enhanced in vitro FcRn binding was mixed, and related to both the strength of charge interaction and the general mechanism predominant in governing the clearance of the particular mAb. Overall, improved pharmacokinetics through enhanced FcRn interactions were apparent for a CDR charge-patch normalized mAb which was affected by non-specific clearance. The findings in this report are an important demonstration that mAb pharmacokinetics requires optimization on a case-by-case basis to improve the design of molecules with increased therapeutic application.     

Stereoselective determination and pharmacokinetics of dihydropyridines: an updated review

All dihydropyridines, except nifedipine, have at least one chiral center, and their pharmacokinetics and clinical effects differ from one enantiomer to another. Chiral separation methods for dihydropyridines using chromatographic techniques are discussed. The stereoselective pharmacokinetics of dihydropyridine calcium antagonists were reviewed in detail in 1995. The present review article updates the methods for the stereoselective determination of dihydropyridines using chromatographic techniques and summarizes the pharmacokinetics of the dihydropyridines, including the newest drugs under development.     

Discovery of zoniporide: a potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility

Zoniporide (CP-597,396) is a potent and selective inhibitor of NHE-1, which exhibits high aqueous solubility and acceptable pharmacokinetics for intravenous administration. The discovery, synthesis, activities, and rat and dog pharmacokinetics of this compound are presented. The potency and selectivity of zoniporide may be due to the conformation that the molecule adopts due to the presence of a cyclopropyl and a 5-quinolinyl substituent on the central pyrazole ring of the molecule.     

Orange juice increased the bioavailability of pravastatin, 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, in rats and healthy human subjects

Our objective was to investigate the effects of orange juice on the pharmacokinetics of pravastatin in rats and healthy volunteers. The pharmacokinetics of pravastatin (100 mg/kg p.o.) were assessed with water, orange juice, and carbohydrates (12.5 ml/kg over 30 min) and with acetic acid (0.1 M, pH 3.44). The pharmacokinetics of simvastatin (100 mg/kg p.o.) were assessed with water and orange juice. In addition, the pharmacokinetics (based on plasma levels) of pravastatin 80 mg/kg i.v. were assessed with water and orange juice (5 ml/kg) in rats. The pharmacokinetics of oral pravastatin (10 mg) were assessed when administered with water and orange juice (800 ml over 3 h) in a two-way crossover study in 14 healthy volunteers. Orange juice significantly increased the area under the curve (0-150 min) of pravastatin in rats. Orange juice had no effects on the pharmacokinetic parameters of intravenously administered pravastatin in rats. Carbohydrates and acetic acid with pH and concentration equivalent to those of orange juice also resulted in no statistically significant differences in pravastatin pharmacokinetic parameters in rats. Orange juice did not result in any significant differences in the pharmacokinetic parameters of simvastatin in rats. Orange juice significantly increased oatp1 and oatp2 mRNA and protein in the intestine of rats. Orange juice significantly increased the area under the curve (0-240 min) of pravastatin in healthy volunteers. In conclusion, orange juice increases the bioavailability of pravastatin administered orally. Oatp1 and oatp2 may be related to increases of pharmacokinetics of pravastatin by orange juice.     

Route-dependent stereoselective pharmacokinetics of tramadol and its active O-demethylated metabolite in rats

The effects of route of administration on the stereoselective pharmacokinetics of tramadol (T) and its active metabolite (M1) were studied in rats. A single 20 mg/kg dose of racemic T was administered through intravenous, intraperitoneal, or oral route to different groups of rats, and blood and urine samples were collected. Samples were analyzed using chiral chromatography, and pharmacokinetic parameters (mean +/- SD) were estimated by noncompartmental methods. Following intravenous injection, there was no stereoselectivity in the pharmacokinetics of T. Both enantiomers showed clearance values (62.5 +/- 27.2 and 64.4 +/- 39.0 ml/min/kg for (+)- and (-)-T, respectively) that were equal or higher than the reported liver blood flow in rats. Similar to T, the area under the plasma concentration-time curves (AUCs) of M1 did not exhibit stereoselectivity after intravenous administration of the parent drug. However, the systemic availability of (+)-T was significantly (P < 0.05) higher than that of its antipode following intraperitoneal (0.527 +/- 0.240 vs. 0.373 +/- 0.189) and oral (0.307 +/- 0.136 vs. 0.159 +/- 0.115) administrations. The AUC of the M1 enantiomers, on the other hand, remained mostly nonstereoselective regardless of the route of administration. Pharmacokinetic analysis indicated that the stereoselectivity in the pharmacokinetics of oral T is due to stereoselective first pass metabolism in the liver and, possibly, in the gastrointestinal tract. The direction and extent of stereoselectivity in the pharmacokinetics of T and M1 in rats were in agreement with those previously reported in humans, suggesting that the rat may be a suitable model for enantioselective studies of T pharmacokinetics.     

Effect of mucin on the pharmacokinetics of antibiotics in the rat

The intramuscular pharmacokinetics of ticarcillin and amikacin in rats receiving 1 ml of 5% mucin suspension (equivalent to 250 mg/kg) administered intraperitoneally were not altered compared with the control animals. However, it is important to investigate the effect of mucin on the pharmacokinetics of antimicrobial agents in animals which are used to evaluate the efficacy of the agents.     

Pharmacokinetic Properties of Phosphorothioate Oligonucleotides

Abstract

The pharmacokinetic parameters determined for different phosphorothioate oligonucleotides were compared. The data suggest that phosphorothioate pharmacokinetics are primarily determined by chemical class. The pharmacokinetics are consistent across species, show dose-dependency, and are independent of sequence.     

A computer system for the storage and retrieval of clinical pharmacokinetic data

A computer system is described which stores patient data relating to clinical pharmacokinetic assessments made by clinical pharmacists, who are participating in a clinical pharmacokinetics service. The system was developed to assist in the documentation of service activities and storage of patients' pharmacokinetic data. An additional component of the system is the ability for retrospective review of the stored data. Applications of this system to the derivation of new information on drug pharmacokinetics and drug efficacy/toxicity in various patient groups is discussed. The implications for Phase IV drug studies and toxicity screening studies is also described.     

Pharmacokinetics of the enantiomers of trans-tramadol and its active metabolite, trans-O-demethyltramadol, in healthy male and female chinese volunteers

By using a high-performance capillary electrophoresis method, the pharmacokinetics of the enantiomers of trans-tramadol (trans-T) and its active metabolite, trans-O-demethyltramadol (M1), was studied in healthy male and female Chinese volunteers after oral administration of 100 mg trans-T hydrochloride. The values of Cmax for the enantiomers of trans-T and M1, and AUC0- infinity for (-)-trans T, (+)-M1, and (-)-M1 were higher in females than in males. The values of V(d)/F for the enantiomers of trans-T and CLr for (+)-M1 were lower in females than in males. The value of t(1/2) for (-)-M1 was longer in females than in males. There were significant differences in pharmacokinetic parameters of the two enantiomers of trans-T or M1 both in males and in females. The (+)/(-)-enantiomeric ratios of t(max), V(d)/F for trans-T in males were significantly different from those in females and the (+)/(-)-enantiomeric ratios of pharmacokinetic parameters for M1 in males were similar to those in females. There are gender-related differences in the pharmacokinetics of the enantiomers of trans-T and M1 which may be due to the greater body weights for men and/or the higher CYP2D6 activity in women. The pharmacokinetics of trans-T and M1 is stereoselective in men and women. There is a gender-related difference in the stereoselectivity in pharmacokinetics of trans-T in human and the stereoselectivity in pharmacokinetics of M1 in men is similar to that in women. Chirality 16:112-118, 2004.     

家兔关节腔中微透析探针植入方法的建立及应用

目的建立家兔关节腔中微透析探针的植入方法,并考察其应用于家兔膝关节局部药动学研究中的可行性。方法将微透析探针在注射针头、引导导管的帮助下从家兔膝关节髌韧带一侧插入关节腔中,并用x．射线检查探针活性透析膜在关节腔中的位置。以青藤碱为研究药物,HPLC—Ms为检测方法同时进行了家兔血液及关节腔局部青藤碱的药动学研究。结果微透析探针活性透析膜能准确地进入关节腔的腔隙中,并成功应用于关节局部药动学研究,得到主要药动学参数。结论家兔关节腔中微透析探针植入方法可行,位置准确,应用于关节局部药动学研究中有明显的优势。     

细胞药代动力学研究进展

经典的药物代谢动力学理论是建立在血浆药物浓度测定的基础上,常难以真实有效地预测体内药物的药效。很多药物必须穿透多重生物屏障,与细胞内的靶点相结合才能发挥药效。因此药代动力学研究迫切需要从“宏观”的血浆药物浓度深入到“微观”的细胞/ 亚细胞水平。综述细胞药代动力学研究领域取得的进展,重点介绍细胞药代动力学理论的提出、技术体系的建立及其在药物研发、筛选、临床方面的应用。     

An ANN model for treatment prediction in HBV patients

Two types of antiviral treatments, namely, interferon and nucleoside/nucleotide analogues are available for hepatitis infections. The selection of drug and dose determined using known pharmacokinetics and pharmacodynamics data is important. The lack of sufficient information for pharmacokinetics of a drug may not produce the desired results. Artificial neural network (ANN) provides a novel model-independent approach to pharmacokinetics and pharmacodynamics data. ANN model is created by supervised learning of 90 patients sample to predict the treatment strategy (lamivudine only and Lamivudine + Interferon) on the basis of viral load, liver function test, visit number, treatment duration, ethnic area, sex, and age. The model was trained with 68 (77.3%) samples and tested with 20 (22.7%) samples. The model produced 92% accuracy with 92.8% sensitivity and 83.3% specificity.     

光敏剂特性影响光动力治疗鲜红斑痣的数学仿真研究

目的：通过建立光动力治疗鲜红斑痣中激光、光敏剂、氧的分布及其相互作用关系的数学模型,对表皮、真皮、血管中单线态氧的产生过程进行仿真,了解光敏剂的药代动力学和扩散特性对单线态氧产生的影响,进而了解光敏剂特性在光动力治疗鲜红斑痣中的作用和意义。方法：用’Monte Carlo方法描述光在组织中的分布;用药代动力学描述光敏剂在血管中的变化规律;用Fick定律描述光敏剂和氧在组织中的扩散和分布;用与氧含量有关的二级动力学描述光敏剂的漂白;用Lambert—Beer定律和单线态氧的量子产率来计算各层组织中单线态氧的产生。结果：光敏剂药代动力学的变化,使注射光敏剂后开始照光的时间对各层组织中单线态氧产量有明显的影响。光敏剂扩散特性的改变,对真皮和表皮中单线态氧的产生有较大影响,对血管中单线态氧的产生没有影响。结论：光敏剂的特性对光动力治疗鲜红斑痣有明显的影响,数学仿真能较全面地反应这种作用的特点和意义。     

Oxygenated analogues of UK-396082 as inhibitors of activated thrombin activatable fibrinolysis inhibitor

A suitable inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa) has the potential to be a novel treatment for thrombosis. The TAFIa inhibitor UK-396082 (1) was used as a starting point to seek more potent analogues. With knowledge of encouraging human pharmacokinetics and toleration for the clinical candidate (1), the programme continued to seek structure–activity relationships (SAR) that could positively impact on both potency and half-life, and therefore the projected dose of any future nominated clinical agent. A series of oxygenated analogues based on compound 1 were prepared to evaluate changes in pharmacology, selectivity and pharmacokinetics.     

In vivo simulation of human pharmacokinetics in the rabbit

The evaluation of drugs in vivo is often based on experimental models using small animals such as mice, rats and rabbits. However, these models could be improved to correspond more closely to the human situation if the pharmacokinetics of the drugs tested in animals were similar to that observed in humans. The use of a computer-controlled pump allowing an adequate flow of tobramycin and amikacin to be infused into rabbits enabled us to simulate the human pharmacokinetics of these antibiotics in vivo in this study. The function defining the rate of infusion required to perform the simulation of an intravenous bolus was first determined generally and symbolically for linear pharmacokinetic models independently from the number of compartments involved. The practical simulation of a decreasing monoexponential serum profile with a half-life of 2 h (one-compartment model for the human pharmacokinetics of aminoglycosides) was then studied for tobramycin and amikacin on the basis of a two-compartment model in the animal. The kinetics obtained had an apparent elimination half-life of 1.97 and 1.86 h, respectively. Linearity of the semilogarithmic regressions of the profiles obtained was quite sound. Finally, an a posteriori analysis of the pharmacokinetic model and its parameters is proposed on the basis of the results obtained after simulation.