光学活性药物的药动学和药效学差异

综述近几年手性药物的研究状况和临床应用结果 ,探讨不同光学活性药动学及药效学特征 ,阐明其药理活性和不良反应实质。近年来的文献报道和临床研究表明有些手性药物在临床上的应用是有益的 ,有些会造成严重后果 ,对手性药物的深入研究将会为临床合理应用手性药物带来积极的意义     

Biopharmaceutics, pharmacokinetics and pharmacodynamics of antituberculosis drugs

Tuberculosis (TB) is the leading cause of mortality due to a single infectious agent. The currently used combination drug regimens produce cure rates that exceed 95%, given good patient adherence during the multiple months treatment period. However the recent surge in HIV infections and the synergy between HIV and TB as well as the emergence of resistance resulted in an unforeseen increase in the number of TB cases, including multi-drug resistant (MDR) and extensively-drug resistant (XDR) forms of TB. Consequently, there is an urgent need to develop novel, fast acting antituberculosis drugs with high potency that can provide treatment options for all forms of TB. It is well known that the current TB drugs exhibit differences in their in vivo activity profile and these differences are largely determined by their pharmacodynamics (PD), i.e. intrinsic antibacterial activity, biopharmaceutical properties such as solubility and permeability, and pharmacokinetic (PK) properties such as drug exposure, tissue distribution, and protein binding. An understanding of the relationships among these properties is considered key for a rational use of antituberculosis therapeutics. The current review provides a comprehensive summary of physicochemical/biopharmaceutical, PK, and PD properties of currently used antituberculosis drugs and novel agents under development. Also, a brief review of PK/PD parameters of current TB drugs is given and properties of a desirable TB drug target and drug molecule are outlined. The information provided herewith may be useful in the optimization of biopharmaceutical and PK/PD characteristics in the development of novel TB therapeutics and in the design of optimal treatment regimens.     

手性药物对映体在药效学与药代动力学的相互作用

当手性药物以外消旋体供药用时，其对映体间就可能发生药效学和药代动力学的相互作用。本文综述了手性药物对映体间的药效学和药代动力学相互作用及其对手性药物药效学和药代动力学立体选择性的影响。     

Stereoselectivity in the pharmacodynamics and pharmacokinetics of the chiral antimalarial drugs

Several of the antimalarial drugs are chiral and administered as the racemate. These drugs include chloroquine, hydroxychloroquine, quinacrine, primaquine, mefloquine, halofantrine, lumefantrine and tafenoquine. Quinine and quinidine are also stereoisomers, although they are given separately rather than in combination. From the perspective of antimalarial activity, most of these agents demonstrate little stereoselectivity in their effects in vitro. Mefloquine, on the other hand, displays in vitro stereoselectivity against some strains of P. falciparum, with a eudismic ratio of almost 2 : 1 in favour of the (+)-enantiomer. Additionally, for some of these agents (e.g. halofantrine, primaquine, chloroquine), stereoselectivity has been noted in the ability of the enantiomers to cause certain adverse effects. In recent years, stereospecific analytical methods capable of measuring the individual enantiomers after the administration of racemic drugs have been reported for a number of chiral antimalarial drugs. These assays have revealed that almost all the studied antimalarial drugs display stereoselectivity in their pharmacokinetics, leading to enantioselectivity in their plasma concentrations. Whereas the oral absorption of these agents appears to be non-stereoselective, stereoselectivity is often seen in their volume of distribution and/or clearance. With regard to distribution, plasma protein binding of some chiral antimalarial drugs exhibits a significant degree of stereoselectivity, leading to stereoselective distribution to blood cells and other tissues. Because of their low hepatic extraction ratios, stereoselective plasma protein binding also contributes to the stereoselectivity in the metabolism of these drugs. Chiral metabolites are formed from some parent antimalarial drugs, although stereoselective aspects of the pharmacokinetics of the metabolites are not well understood. It is concluded that knowledge of the stereoselective aspects of these agents may be helpful in better understanding their mechanisms of action and possibly optimising their clinical safety and/or effectiveness.     

芳基烷酸类非甾体抗炎药的手性药动学和药效学研究

非甾体抗炎药(nonsteroidal antiinflammatory drugs,NSAIDs)是一类常见的具有抗炎、解热、镇痛及抗风湿作用的药物,临床应用广泛.大多数芳基烷酸类非甾体抗炎药都具有手性,它们的2个对映体在体内的药理活性、代谢过程及不良反应存在显著的差异.文中对常见芳基烷酸类NSAID对映体的药效学和药动学特点,年龄、性别、疾病状态等因素对其药动学过程的影响,以及临床应用进行了综述.     

Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs

The multi-drug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette (ABC) superfamily of membrane transporters. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multi-drug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of various types of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and indicated that a single nucleotide polymorphism (SNP), C3435T in exon 26, which caused no amino acid change, was associated with the duodenal expression of MDR1 and thereby the plasma concentrations of digoxin after oral administration. Interethnic differences in genotype frequencies of C3435T have been clarified, and, at present, a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on the effects of C3435T on MDR1 expression and function in the tissues, and also on the pharmacokinetics and pharmacodynamics have been performed around the world; however, there are still discrepancies in the results, suggesting that the haplotype analysis of the gene should be included instead of SNP detection, and the design of clinical trials must be carefully planned to avoid misinterpretations. A polymorphism of C3435T is also reported to be a risk factor for a certain class of diseases such as the inflammatory bowel diseases, Parkinson's disease and renal epithelial tumor, and this might also be explained by the effects on MDR1 expression and function. In this review, the latest reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping.     

Impact of disease states on the pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors

The pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors (ACE) in elderly patients and patients with renal and hepatic impairment were examined, and a role for an AUC/EC50 ratio to guide dosing was evaluated. A Medline and International Pharmaceutical Abstracts search was used to identify human studies and abstracts. Relevant data were evaluated and summarized. Dosing regimens were compared using an AUC/EC50 ratio. Most studies evaluating ACE inhibitors in renal impairment report a strong linear correlation between creatine clearance and drug elimination. AUC and EC50 values for these drugs in elderly subjects appear similar to younger and hypertensive patients. There is increased AUC in some patients with hepatic impairment. Pharmacodynamic data are conflicting. Prolonged ACE inhibition is evident in renal impairment but not necessarily other disease states. ACE inhibitor dosing for hypertension is reasonable based on pharmacokinetics and EC50 values. Further individualization of therapy may improve outcomes, and using the threshold AUC/EC50 ratio may help guide appropriate dosing.     

手性药物的药代动力学立体选择性及其影响因素研究进展

药代动力学立体选择性是指手性药物对映体在吸收、分布、代谢和消除过程中有差异。本文综述了手性药物药代动力学立体选择性及其影响因素方面的最新研究进展。     

Antibody pharmacokinetics and pharmacodynamics

The U.S. Food and Drug administration (FDA) has approved several polyclonal antibody preparations and at least 18 monoclonal antibody preparations (antibodies, antibody fragments, antibody fusion proteins, etc.). These drugs, which may be considered as a diverse group of therapeutic proteins, are associated with several interesting pharmacokinetic characteristics. Saturable binding with target antigen may influence antibody disposition, potentially leading to nonlinear distribution and elimination. Independent of antigen interaction, concentration-dependent elimination may be expected for IgG antibodies, due to the influence of the Brambell receptor, FcRn, which protects IgG from catabolism. Antibody administration may induce the development of an endogenous antibody response, which may alter the pharmacokinetics of the therapeutic antibody. Additionally, the pharmacodynamics of antibodies are also complex; these drugs may be used for a wide array of therapeutic applications, and effects may be achieved by a variety of mechanisms. This article provides an overview of many of the complexities associated with antibody pharmacokinetics and pharmacodynamics.     

Multidrug resistance associated proteins as determining factors of pharmacokinetics and pharmacodynamics of drugs

The multidrug resistance associated proteins (MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, MRP8 and MRP9) belong to the ATP-binding cassette superfamily (ABCC family) of transporters. They are expressed differentially in the liver, kidney, intestine, brain and other tissues. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. Several MRPs (mainly MRP1-3) are associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. MRPs transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. Most MRPs are subject to induction and inhibition by a variety of compounds. Several nuclear receptors, including pregnane X receptor (PXR), liver X receptor (LXR), and farnesoid receptor (FXR) participate in the regulation of MRPs. MRPs play an important role in the absorption, distribution and elimination of various drugs in the body and thus may affect their efficacy and toxicity and cause drug-drug interactions. MRPs located in the blood-brain barrier can restrict the penetration of compounds into the central nervous system. Mutation of MRP2 causes Dubin-Johnson syndrome, while mutations in MRP6 are responsible for pseudoxanthoma elasticum. More recently, mutations in mouse Mrp6/Abcc6 gene is associated with dystrophic cardiac calcification (DCC), a disease characterized by hydroxyapatite deposition in necrotic myocytes. A single nucleotide polymorphism, 538G>A in the MRP8/ABCC11 gene, is responsible for determination of earwax type. A better understanding of the function and regulating mechanism of MRPs can help minimize and avoid drug toxicity, unfavourable drug-drug interactions, and to overcome drug resistance.     

Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether-lumefantrine.

The combination of artemether and lumefantrine (benflumetol) is a new and very well tolerated oral antimalarial drug effective even against multidrug-resistant falciparum malaria. The artemether component is absorbed rapidly and biotransformed to dihydroartemisinin, and both are eliminated with terminal half-lives of around 1 hour. These are very active antimalarials which give a rapid reduction in parasite biomass and consequent rapid resolution of symptoms. The lumefantrine component is absorbed variably in malaria, and is eliminated more slowly (half-life of 3 to 6 days). Absorption is very dependent on coadministration with fat, and so improves markedly with recovery from malaria. Thus artemether clears most of the infection, and the lumefantrine concentrations that remain at the end of the 3- to 5-day treatment course are responsible for eliminating the residual 100 to 10 000 parasites. The area under the curve of plasma lumefantrine concentrations versus time, or its correlate the plasma concentration on day 7. has proved an important determinant of therapeutic response. Characterisation of these pharmacokinetic-pharmacodynamic relationships provided the basis for dosage optimisation, an approach that could be applied to other antimalarial drugs.     

The altered pharmacokinetics and pharmacodynamics of drugs commonly used in critically ill patients

The critically ill patient occupies an increasing amount of time and bed space in modern hospital practice, and also commands increasing expenditure. Drug therapy in these patients has, in the past, been based on data derived from healthy volunteers, fit anaesthetised patients undergoing minor operative procedures, or patients with single organ failure. Alterations in pharmacokinetics and pharmacodynamics have not been studied in depth in critically ill patients who often have multisystem failure. This paper reviews the currently available information on drugs in common usage in these patients. The studies that have been performed have usually shown delayed drug clearance, altered volumes of distribution and prolonged elimination half-lives. The sedative and analgesic drugs, in particular, have shown marked accumulation which may confuse the clinical picture, and prolonged periods of assisted ventilation may be required until the drugs are eliminated.     

Modelling the pharmacokinetics and pharmacodynamics of trimazosin

The pharmacokinetics and pharmacodynamics of trimazosin are described following both intravenous and oral administration to 6 normotensive, male volunteers. The IV and oral drug and metabolite (1-hydroxytrimazosin) concentration data are fitted simultaneously to the same pharmacokinetic model. The pharmacodynamic response, change in systolic blood pressure following 5 min in the erect posture, is described using several possible models. The most efficient is one which attributes the response to both the parent drug and its principal metabolite. The response following oral administration is also consistent with this model. It appears that the reduction in blood pressure following administration of trimazosin at steady state may be governed by the concentration of metabolite.     

Electroencephalogram effect measures and relationships between pharmacokinetics and pharmacodynamics of centrally acting drugs.

Electroencephalogram (EEG) effect parameters may be useful in pharmacokinetic-pharmacodynamic modelling studies of drug effects on the central nervous system (CNS). Effect parameters derived from a quantitative analysis of the EEG appear to be perfectly suited to characterise the relationships between pharmacokinetics and pharmacodynamics of benzodiazepines and intravenous anaesthetics. EEG parameters represent many of the characteristics of ideal pharmacodynamic measures, being continuous, objective, sensitive and reproducible. These features provide the opportunity to derive concentration-effect relationships for these drugs in individuals, which yield important quantitative information on the potency and intrinsic efficacy of these drugs. The EEG techniques presented can be used to study the influences of factors such as age, disease, chronic drug use and drug interactions on the concentration-effect relationships of psychotropic drugs. An important issue is the choice of the EEG parameter to characterise the CNS effects of the compounds. More attention must be paid to evaluating the relevance of EEG parameters to the pharmacological effects of the drugs. Knowledge of the relationship between EEG effect parameters and clinical effects of drugs under different physiological and pathophysiological conditions is crucial to determining the value of EEG parameters in drug effect monitoring. Pharmacodynamic parameters derived from the concentration-EEG effect relationship may be correlated to pharmacodynamic parameters obtained from other in vitro and in vivo effect measurements. These comparisons revealed that changes in the amplitudes in the beta frequency band of EEG signals is a relevant measure of pharmacological effect intensity of benzodiazepines, which reflects their affinity and intrinsic efficacy at the central gamma-aminobutyric acid (GABA) benzodiazepine receptor complex. The exact EEG correlates of the anxiolytic, anticonvulsant, sedative and hypnotic actions of benzodiazepines have not yet clearly been elucidated. For intravenous anaesthetics, close correlations between the potency determined with EEG measurements and clinical measures of anaesthetic depth have been established, suggesting that, in principle, EEG parameters can adequately reflect depth of anaesthesia. However, more study is required to further substantiate these findings.     

Macrolides: pharmacokinetics and pharmacodynamics

Three pharmacokinetic/pharmacodynamic parameters--(i) the peak concentration to the minimum inhibitory concentration ratio (C(max)/MIC); (ii) the area under the concentration-time curve to MIC ratio (AUC(24h)/MIC); and (iii) the time the concentration exceeds the MIC (T>MIC)--are important predictors of the clinical efficacy of antibiotics. For antibiotics with pronounced concentration-dependent killing, such as the fluoroquinolones or the aminoglycosides, C(max)/MIC and AUC(24)/MIC are the main factors that establish efficacy. Antibiotics with a weak, or no, concentration dependency generally have their efficacy linked to T>MIC, and these include the beta-lactams and the conventional macrolides. Antibiotics with weak concentration-dependent effects, but with prolonged persistent effects, such as tetracyclines and azithromycin, have their activity mostly related to the AUC(24)/MIC. By applying these concepts to current antibiotics, and also to the development of novel agents, it is possible to optimise their dosages and administration schedules. This will maximise therapeutic efficacy, may prevent or delay the emergence of bacterial resistance to antibiotics, and can certainly minimise side-effects.     

Heparin pharmacokinetics and pharmacodynamics.

Heparin was discovered approximately 75 years ago and has been used extensively for the last 50 years to treat thromboembolic disorders. An endogenous glycosaminoglycan, heparin is found largely in the liver, lung and intestine. It is available for exogenous administration both as unfractionated and low molecular weight heparin. Unfractionated heparin is a heterogenous mixture of polysaccharide chains of varying length resulting in a range of molecular weights from 3000 to 30,000D while low molecular weight heparin ranges from 3000 to 6000D. Heparin produces its antithrombotic effect by binding to antithrombin III and this complex then binds to thrombin. In order to accomplish this a total of 18 to 22 monosaccharide units is necessary including a specific pentasaccharide binding site for antithrombin III. After either subcutaneous or intravenous injection heparin is distributed primarily within the intravascular space. A short distribution phase is seen which is thought to correspond to endothelial cell binding and internalisation. The disposition curve for unfractionated heparin has a unique concave-convex shape which is the result of combined saturable and nonsaturable elimination mechanisms. The nonsaturable elimination mechanism is renal and is the primary route of elimination for low molecular weight heparins. For this reason, the concave-convex pattern is not seen with low molecular weight preparations. Both forms of heparin are useful antithrombotic agents; however, the correlation between the antithrombotic effect and an in vitro laboratory test for either type still needs further clarification.     

Effect of rosuvastatin on warfarin pharmacodynamics and pharmacokinetics

The effect of rosuvastatin on warfarin pharmacodynamics and pharmacokinetics was assessed in 2 trials. In trial A (a randomized, double-blind, 2-period crossover study), 18 healthy volunteers were given rosuvastatin 40 mg or placebo on demand (o.d.) for 10 days with 1 dose of warfarin 25 mg on day 7. In trial B (an open-label, 2-period study), 7 patients receiving warfarin therapy with stable international normalized ratio values between 2 and 3 were coadministered rosuvastatin 10 mg o.d. for up to 14 days, which increased to rosuvastatin 80 mg if the international normalized ratio values were <3 at the end of this period. The results indicated that rosuvastatin can enhance the anticoagulant effect of warfarin. The mechanism of this drug-drug interaction is unknown. Rosuvastatin had no effect on the total plasma concentrations of the warfarin enantiomers, but the free plasma fractions of the enantiomers were not measured. Appropriate monitoring of the international normalized ratio is indicated when this drug combination is coadministered.