Genetic polymorphisms of drug transporters: pharmacokinetic and pharmacodynamic consequences in pharmacotherapy

There has been increasing appreciation of the role of drug transporters in pharmacokinetic and pharmacodynamic consequences in pharmacotherapy. The clinical relevance of drug transporters depends on the localisation in human tissues (i.e., vectorial movement), the therapeutic index of the substrates and inherent interindividual variability. With regard to variability, polymorphisms of drug transporter genes have recently been reported to be associated with alterations in the pharmacokinetics and pharmacodynamics of clinically useful drugs. A growing number of preclinical and clinical studies have demonstrated that the application of genetic information may be useful in individualised pharmacotherapy for numerous diseases. However, the reported effects of variants in certain drug transporter genes have been inconsistent and, in some cases, conflicting among studies. Furthermore, the incidence of almost all known variants in transporter genes tends to be racially dependent. These observations suggest the necessity of considering interethnic variability before extrapolating pharmacokinetic data obtained in one ethic group to another, especially in the early phase of drug development. This review focuses on the impact of genetic variations in the function of drug transporters (ABC, organic anion and cation transporters) and the implications of these variations for pharmacotherapy from pharmacokinetic and pharmacodynamic viewpoints.     

Effect of diabetes mellitus on pharmacokinetic and pharmacodynamic properties of drugs

The effects of diabetes mellitus on the pharmacokinetics and pharmacodynamics of drugs have been well described in experimental animal models; however, only minimal data exist for humans and the current knowledge regarding the effects of diabetes on these properties remains unclear. Nevertheless, it has been observed that the pharmacokinetics and pharmacodynamics of drugs are changed in subjects with diabetes. It has been reported that diabetes may affect the pharmacokinetics of various drugs by affecting (i) absorption, due to changes in subcutaneous adipose blood flow, muscle blood flow and gastric emptying; (ii) distribution, due to non-enzymatic glycation of albumin; (iii) biotransformation, due to regulation of enzymes/transporters involved in drug biotransformation; and (iv) excretion, due to nephropathy. Previously published data also suggest that diabetes-mediated changes in the pharmacokinetics of a particular drug cannot be translated to others. Although clinical studies exploring the effect of diabetes on pharmacodynamics are still very limited, there is evidence that disease-mediated effects are not limited only to pharmacokinetics but also alter pharmacodynamics. However, for many drugs it remains unclear whether these influences reflect diabetes-mediated changes in pharmacokinetics rather than pharmacodynamics. In addition, even though diabetes-mediated pharmacokinetics and pharmacodynamics might be anticipated, it is important to study the effect on each drug and not generalize from observed data. The available data indicate that there is a significant variability in drug response in diabetic subjects. The discrepancies between individual clinical studies as well as between ex vivo and clinical studies are probably due to (i) the restricted and focused population of subjects in clinical studies; (ii) failure to consider type, severity and duration of the disease; (iii) histopathological characteristics generally being missing; and (iv) other factors such as varying medication use, dietary protein intake, age, sex and obesity. The obesity epidemic in the developed world has also inadvertently influenced the directions of pharmacological research. This review attempts to map new information gained since Gwilt published his paper in Clinical Pharmacokinetics in 1991. Although a large body of research has been conducted and significant progress has been made, we still have to conclude that the available information regarding the effect of diabetes on pharmacokinetics and pharmacodynamics remains unclear and further clinical studies are required before we can understand the clinical significance of the effect. An understanding of diabetes-mediated changes as well as of the source of the variability should lead to the improvement of the medical management and clinical outcomes in patients with this widespread disease.     

Statistical learning approach for predicting specific pharmacodynamic,pharmacokinetic, or toxicological properties of pharmaceutical agents

Pharmaceutical agents have been developed and tested for possessing desirable pharmacodynamic, pharmacokinetic, and minimal level of toxicological properties. Computational methods have been explored for predicting these properties aimed at the discovery of promising leads and the elimination of unsuitable ones in early stages of drug development. Statistical learning methods have shown their potential for predicting these properties for structurally diverse sets of agents by using both conventional (quantitative structure–activity and structure–property relationships) and more recently explored (such as neural networks and support vector machines) statistical models. These methods have been used for predicting agents of a variety of pharmacodynamic (such as inhibitors or agonists of a therapeutic target), pharmacokinetic (such as P‐glycoprotein substrates, human intestine absorption, and blood–brain barrier penetrating capabilities), and toxicological (such as genotoxicity) properties. The strategies, current progresses, and the underlying difficulties and future prospects of the application of the recently explored statistical learning methods are discussed. Drug Dev. Res. 66:245–259, 2006. © 2006 Wiley‐Liss, Inc.     

Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences

To clarify the considerable interindividual variability in the pharmacokinetics, efficacy, and toxicity of drugs, genetic polymorphism of drug transporters has attracted interest because these transporters play important roles in the gastrointestinal absorption, biliary and renal elimination, and distribution to target sites of their substrates. Of the over 325 members of the solute carrier superfamily, this review focuses on the molecular features, expressional regulation, and genetic polymorphisms of the organic cation transporter (OCT) family, and the pharmacokinetic or pharmacodynamic consequences for organic cationic drugs. Although the clinical significance is still unclear, many studies have reported the importance of OCTs in the tissue distribution and elimination of their substrates in vitro and in vivo, and the impact of functional non-synonymous single nucleotide polymorphisms or differential expression levels of OCTs on the large interindividual variation in the pharmacokinetics and response of organic cationic drugs such as metformin, imatinib, and cisplatin.     

Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease

Current research in Parkinson's disease (PD) focuses on symptomatic therapy and neuroprotective interventions. Drugs that have been used for symptomatic therapy are levodopa, usually combined with a peripheral decarboxylase inhibitor, synthetic dopamine receptor agonists, centrally-acting antimuscarinic drugs, amantadine, monoamine oxidase-B (MAO-B) inhibitors and catechol-O-methyltransferase (COMT) inhibitors. Drugs for which there is at least some evidence for neuroprotective effect are certain dopamine agonists, amantadine and MAO-B inhibitors (selegiline). Levodopa remains the most effective drug for the treatment of PD. Several factors contribute to the complex clinical pharmacokinetics of levodopa: erratic absorption, short half-life, peripheral O-methylation and facilitated transport across the blood-brain barrier. In patients with response fluctuations to levodopa, the concentration-effect curve becomes steeper and shifts to the right compared with patients with stable response. Pharmacokinetic-pharmacodynamic modelling can affect decisions regarding therapeutic strategies. The dopamine agonists include ergot derivatives (bromocriptine, pergolide, lisuride and cabergoline), non-ergoline derivatives (pramipexole, ropinirole and piribedil) and apomorphine. Most dopamine agonists have their specific pharmacological profile. They are used in monotherapy and as an adjunct to levodopa in early and advanced PD. Few pharmacokinetic and pharmacodynamic data are available regarding centrally acting antimuscarinic drugs. They are characterised by rapid absorption after oral intake, large volume of distribution and low clearance relative to hepatic blood flow, with extensive metabolism. The mechanism of action of amantadine remains elusive. It is well absorbed and widely distributed. Since elimination is primarily by renal clearance, accumulation of the drug can occur in patients with renal dysfunction and dosage reduction must be envisaged. The COMT inhibitors entacapone and tolcapone dose-dependently inhibit the formation of the major metabolite of levodopa, 3-O-methyldopa, and improve the bioavailability and reduce the clearance of levodopa without significantly affecting its absorption. They are useful adjuncts to levodopa in patients with end-of-dose fluctuations. The MAO-B inhibitor selegiline may have a dual effect: reducing the catabolism of dopamine and limiting the formation of neurotoxic free radicals. The pharmacokinetics of selegiline are highly variable; it has low bioavailability and large volume of distribution. The oral clearance is many-fold higher than the hepatic blood flow and the drug is extensively metabolised into several metabolites, some of them being active. Despite the introduction of several new drugs to the antiparkinsonian armamentarium, no single best treatment exists for an individual patient with PD. Particularly in the advanced stage of the disease, treatment should be individually tailored.     

Moclobemide: evolution,pharmacodynamic, and pharmacokinetic properties

The benzamide moclobemide is a reversible inhibitor of monoamine-oxidase-A (RIMA). It has been extensively evaluated in the treatment of a wide spectrum of depressive disorders and less extensively in anxiety disorders. While clinical aspects will be presented in a subsequent review, this article focuses primarily on moclobemide's evolution, pharmacodynamic and pharmacokinetic properties. In particular, the effects on neurotransmission and intracellular signal transduction, the neuroendocrine system, the tyramine pressure response and animal models of depression are surveyed. In addition, other CNS effects are reviewed with special respect to experimental serotonergic syndrome, anxiolytic and antinociceptive activity, sleep, cognition and driving performance, neuroprotection and seizures.     

Regression methods for developing QSAR and QSPR models to predict compounds of specific pharmacodynamic, pharmacokinetic and toxicological properties

Quantitative structure-activity relationship (QSAR) and quantitative structure-property relationship (QSPR) models have been extensively used for predicting compounds of specific pharmacodynamic, pharmacokinetic, or toxicological property from structure-derived physicochemical and structural features. These models can be developed by using various regression methods including conventional approaches (multiple linear regression and partial least squares) and more recently explored genetic (genetic function approximation) and machine learning (k-nearest neighbour, neural networks, and support vector regression) approaches. This article describes the algorithms of these methods, evaluates their advantages and disadvantages, and discusses the application potential of the recently explored methods. Freely available online and commercial software for these regression methods and the areas of their applications are also presented.     

Amphiphilic drugs. 2. Relation between colloidal properties and pharmaceutic-technological, pharmacokinetic and pharmacodynamic behavior

The physicochemical properties of amphiphilic drugs may affect the technological, pharmacokinetic and pharmacodynamic behaviours. Micelle formation of a drug is of considerable importance for its solubility, stability, adsorption pattern, mixed micelle formation and influences thus its pharmaceutical availability. The biological availability is in many cases decreased by interactions of a surface active drug with other substances before absorption, by altered diffusion behaviour and distribution properties. Colloidal association may also result in an alteration of pharmacodynamic effects. These relations depend on the fact, that discrete hydrophobic an hydrophilic parts in a molecule are also prerequisites for micelle formation and receptor interactions. Furthermore the high membrane affinity of these drugs is responsible for some therapeutic and toxic effects.     

Functional characteristics and pharmacokinetic significance of kidney-specific organic anion transporters, OAT-K1 and OAT-K2, in the urinary excretion of anionic drugs

During the last decade, cDNA cloning has identified various gene families of drug transporters, and pharmacokinetic studies of drugs based on the molecular characteristics of transporters have advanced. We cloned and characterized two organic anion transporters OAT-K1 and OAT-K2 from the rat kidney. The expression of both transporters was limited to the kidney, especially the brush-border membranes of proximal tubules, with an apparent molecular mass of 40 kDa. Using MDCK or LLC-PK1 cells stably expressing OAT-K1, posttranslational cleavage was suggested to affect the membrane localization and functional characteristics; 50 kDa with multispecificity in the apical membrane of MDCK cells and 70 kDa with methotrexate specific transport in the basolateral membrane of LLC-PK1 cells. A wide variety of anionic compounds including methotrexate are bidirectionally transported via OAT-K1 and OAT-K2 across the apical membrane in the MDCK-transfectants. The urinary secretion of methotrexate was depressed in 5/6 nephrectomized rats in association with the selective loss of OAT-K1 and OAT-K2 expression, and both transporters were suggested to be target molecules for methotrexate-folinic acid rescue. In this review, recent advances in the study of OAT-K1 and OAT-K2 were summarized in comparison with other transporters.     

Effects of sex on the pharmacokinetic and pharmacodynamic properties of quinidine

AIMS: To investigate the source of the apparent increased susceptibility of women to develop QT interval prolongation and torsade de pointes after the administration of drugs that delay cardiac repolarization. METHODS: Plasma quinidine concentrations and electrocardiographic changes (QRS and QT intervals) were measured over 24 h following the administration of single oral doses of the QT prolonging drug quinidine (3 mg kg(-1)) and compared between 27 male and 21 female healthy volunteers. RESULTS: There were no significant differences between males and females in plasma quinidine concentrations or in calculated pharmacokinetic variables. Maximum quinidine concentrations in males and females were 997 +/- 56 and 871 +/- 57 ng ml(-1), respectively (mean difference (-125, 95% confidence intervals (CI) -239, 11 ng ml(-1), P = NS). Quinidine lengthened actual (QTa) and corrected (QTc) QT intervals and the QRS interval to a greater extent in females than males (P < 0.001 for each), but there were no significant sex differences detected in the effects of quinidine on the heart rate corrected JT interval. Maximum prolongation of QTc interval was observed 2 h after quinidine and was significantly greater in women (33 +/- 16 vs 24 +/- 17 ms, mean difference 9 +/- 20 ms, 95% CI 3, 15, P = 0.037). At this time mean differences (95% CI) were 1.0 min(-1) (-2.5, 4.4, P = NS) for heart rate, 5.5 ms (3.5, 7.6, P = 0.05) for the QRS and 3.4 ms (-2.5, 9.3, P = NS) for the JTc intervals. CONCLUSIONS: Quinidine-induced increases in QTc were larger in females, but no sex differences in quinidine pharmacokinetics were found. The disparity in prolongation of cardiac repolarization is thus due to a pharmacodynamic difference which appears more complex than simply an increase in repolarization delay in females.     

Prediction of compounds with specific pharmacodynamic, pharmacokinetic or toxicological property by statistical learning methods

Computational methods for predicting compounds of specific pharmacodynamic, pharmacokinetic, or toxicological property are useful for facilitating drug discovery and drug safety evaluation. The quantitative structure-activity relationship (QSAR) and quantitative structure-property relationship (QSPR) methods are the most successfully used statistical learning methods for predicting compounds of specific property. More recently, other statistical learning methods such as neural networks and support vector machines have been explored for predicting compounds of higher structural diversity than those covered by QSAR and QSPR. These methods have shown promising potential in a number of studies. This article is intended to review the strategies, current progresses and underlying difficulties in using statistical learning methods for predicting compounds of specific property. It also evaluates algorithms commonly used for representing structural and physicochemical properties of compounds.     

Use of molecular topology for the prediction of physico-chemical,pharmacokinetic and toxicological properties of a group of antihistaminic drugs

We used molecular connectivity to search mathematical models for predicting physico-chemical (e.g. the partition coefficient, P), pharmacokinetic (e.g. the time of maximum plasma level, and toxicological properties (lethal dose, LD) for a group of antihistaminic drugs. The results obtained clearly reveal the high efficiency of molecular topology for the prediction of these properties. Randomization and cross-validation by use of leave-one-out tests were also performed in order to assess the stability and the prediction ability of the connectivity functions selected.     

Animal-to-human extrapolation of the pharmacokinetic and pharmacodynamic properties of buprenorphine

OBJECTIVES: This investigation describes the interspecies scaling of the pharmacokinetics and pharmacodynamics of buprenorphine. METHODS: Data on the time course of the antinociceptive and respiratory depressant effects of buprenorphine in rats and in humans were simultaneously analysed on the basis of a mechanism-based pharmacokinetic-pharmacodynamic model. RESULTS: An allometric three-compartment pharmacokinetic model described the time course of the concentration in plasma. The value of the allometric coefficient for clearance was 35.2 mL/min (relative standard error [RSE] = 5.6%) and the value of the allometric exponent was 0.76 (RSE 5.61%). A combined biophase distribution-receptor association/dissociation model with a linear transduction function described hysteresis between plasma concentration and effect. The values of the drug-specific pharmacodynamic parameters were identical in rats and in humans. For the respiratory depressant effect, the values of the second-order rate constant of receptor association (k(on)) and the first-order rate constant of receptor dissociation (k(off)) were 0.23 mL/ng/min (RSE = 15.8%) and 0.014 min(-1) (RSE = 27.7%), respectively, and the value of the equilibrium dissociation constant (K(diss)) was 0.13 nmol/L. The value of the intrinsic activity alpha was 0.52 (RSE = 3.4%). For the antinociceptive effect, the values of the k(on) and k(off) were 0.015 mL/ng/min (RSE = 18.3%) and 0.053 min(-1) (RSE = 23.1%), respectively. The value of the K(diss) was 7.5 nmol/L. An allometric equation described the scaling of the system-specific parameter, the first-order distribution rate constant (k(e0)). The value of the allometric coefficient for the k(e0) was 0.0303 min(-1) (RSE = 11.3%) and the value of the exponent was -0.28 (RSE = 9.6%). CONCLUSIONS: The different values of the drug-specific pharmacodynamic parameters are consistent with the different opioid mu receptor subtypes involved in the antinociceptive and respiratory depressant effects.     

Theoretical pharmacokinetic and pharmacodynamic simulations of drug delivery mediated by blood--brain barrier transporters

Pharmacokinetic/pharmacodynamic simulations were performed to assess the feasibility of central nervous system (CNS) drug delivery via endogenous transporters resident at the blood-brain barrier (BBB). Pharmacokinetic models were derived for intravenous bolus dosing of a hypothetical drug in the absence or presence of an endogenous, competing transport inhibitor. These models were linked to CNS pharmacodynamic models where the effect sites were either cell surface receptors or intracellularly localized enzymes. The response of the dependent parameter, the duration of effect (t(dur)), was examined in relationship to changes in the independent parameters, i.e. dose, elimination rate constant (k(e1)), BBB transport parameters (K(m1) and V(max1)) and EC(50) (effective concentration that elicits a 50% response). As expected, t(dur) increased with (a) increases in drug doses, (b) decreases in k(e1) or (c) decreases in EC(50), irrespective of the effect site. Surprisingly, endogenous transport inhibition produced decreases in drug terminal half-life and corresponding decreases in t(dur). Interestingly, t(dur) was independent of assigned transporter K(m) and V(max) when the dose/EC(50) ratio (dose/EC(50)) was >1 (irrespective of endogenous transport inhibition), but highly dependent on K(m1) and V(max1) when dose/EC(50) was (a) <1 (no endogenous transport inhibition) or (b) equal to 1 (with endogenous transport inhibition). Oral input of the endogenous transport inhibitor produced a decrease in t(dur) when the dose/EC(50) range was 0.1-10. These simulations highlight that (a) systemic pharmacokinetic and BBB transport parameters influence t(dur), (b) drug terminal half-life is inversely related to circulating levels of endogenous inhibitors, and (c) oral ingestion of endogenous transport inhibitor(s) reduces t(dur). Overall, these simulations provide insight for the feasibility of rational CNS drug design/delivery via endogenous transporters.     

Individualized dosage regimen of immunosuppressive drugs based on pharmacokinetic and pharmacodynamic analysis

The calcineurin inhibitors cyclosporine and tacrolimus are widely used to prevent allograft rejection after transplantation. Since these drugs have narrow therapeutic windows and show considerable pharmacokinetic variability, therapeutic drug monitoring (TDM) is essential to avoid adverse effects such as nephrotoxicity while maximizing immunosuppressive efficacy. On the other hand, some patients experience acute rejection episodes or postoperative complications despite achieving therapeutic blood drug levels. Therefore, pharmacokinetic and pharmacodynamic factors by which to establish individualized dosage adjustment for these drugs should be identified. Recently, it was recognized that pharmacogenomics has the potential to facilitate personalized medicine by translating knowledge of human genome variability into rational therapeutics. In this paper, we review the population pharmacokinetic and pharmacogenomic analysis of tacrolimus, focusing on an efflux transporter P-glycoprotein (multidrug resistance 1 [MDR1/ABCB1]) and drug-metabolizing enzymes cytochrome P450 (CYP) 3A4 and 3A5, and describe Bayesian forecasting to individualize the tacrolimus dose in de novo living-donor liver transplant recipients. Furthermore, the pharmacodynamic properties of tacrolimus and cyclosporine, which were evaluated by measuring calcineurin phosphatase activity in peripheral blood mononuclear cells, are reviewed in relation to an optimal monitoring strategy as well as a rational dosage regimen for these drugs.     

Relationship of pharmacokinetic and pharmacodynamic properties of the organic nitrates

Glyceryl trinitrate (nitroglycerin), isosorbide dinitrate and isosorbide mononitrate are, in various formulations, available for clinical use. The pharmacokinetics of glyceryl trinitrate are complex and only 1% of the drug administered orally can be detected in the plasma due to a pronounced arteriovenous concentration gradient, hydrolysis in the blood, and rapid denitration in the liver. There is a poor and usually transient correlation between plasma concentrations and therapeutic effects, due in part to the complex pharmacokinetics of glyceryl trinitrate, but primarily due to development of tolerance during continuous administration, either via the intravenous or cutaneous route. Isosorbide dinitrate kinetics are complicated by its extensive metabolism into 2- and 5-mononitrates, which are pharmacologically active, and which also accumulate more than the parent drug during long term treatment. These facts, combined with development of tolerance during long term therapy, preclude the establishment of a concentration-response relationship. Isosorbide-5-mononitrate has ideal and dose-linear kinetics and is nearly 100% bioavailable after oral administration. However, tolerance develops during long term therapy, and therefore a relationship between plasma concentrations and clinical effects cannot be established. On the basis of available data, plasma concentrations of various nitrates do not reliably predict clinical effects.     

Species differences in pharmacokinetic and pharmacodynamic properties of nebicapone

The present study was designed to characterize pharmacodynamic and pharmacokinetic properties of nebicapone in rats and mice. Upon oral administration of nebicapone the extent of mouse liver catechol-O-methyltransferase (COMT) inhibition is half that in the rat. Nebicapone was rapidly absorbed reaching plasma C_max within 30 min and being completely eliminated by 8 h. Nebicapone was metabolized mainly by glucuronidation and methylation in both species, but rat had an extra major metabolite, resulting from sulphation. Administration of nebicapone by the intraperitoneal route significantly increased compound AUC in the rat while in the mouse a significant increase in AUC of metabolites was observed. These results show that nebicapone exhibited marked species differences in bioavailability and metabolic profile. Evaluation of COMT activity in rat and mice liver homogenates revealed that both had similar methylation efficiencies (K_cat values, respectively 7.3 and 6.4 min⁻¹), but rat had twice active enzyme units as the mouse (molar equivalency respectively 150 and 83). Furthermore, nebicapone inhibited rat liver COMT with a lower K_i than mouse liver COMT (respectively 0.2 nM vs. 1.2 nM). In conclusion, the results from the present study show that mice and rats respond differently to COMT inhibition by nebicapone. The more pronounced inhibitory effects of nebicapone in the rat may be related to an enhanced oral availability and less pronounced metabolism of nebicapone in this specie, but also concerned with the predominant expression of S-COMT over MB-COMT, the latter of which is less sensitive to inhibition by nebicapone than the former.     

Tramadol--the impact of its pharmacokinetic and pharmacodynamic properties on the clinical management of pain

Tramadol (CAS 36282-47-0) plays an important role in the management of pain. With its dual mechanism of action (opioid agonist; weak noradrenaline and serotonin reuptake inhibitor) tramadol provides a kind of combined/adjuvant pain therapy. Besides its proven clinical efficacy tramadol is a safe drug as respiratory depression, cardiovascular side effects, drug abuse and dependence are of minor clinical relevance, unlike some other opioids. Following oral administration the bioavailability of tramadol is high (70-90%) and with new slow release preparations twice daily administration enables effective pain control. Tramadol is characterised by low plasma protein binding (20%) and quite extensive tissue distribution (apparent volume of distribution about 3 l/kg). Elimination is primarily by the hepatic route (metabolism by CYP2D6 to an active metabolite and by CYP3A4 and CYP2B6) and partly by the renal route (up to 30% of dose). Elimination half-lives of the active agents range between 4.5 and 9.5 h and total plasma clearance of tramadol is moderately high (600 ml/min). The interaction potential of tramadol is neglectable, as it does not affect the disposition of other drugs. It should be taken into account that inducers (e.g. carbamazepine) or inhibitors (e.g. quinidine for CY2D6) of drug metabolism might modify the elimination of tramadol. Likewise, if kidney (creatinine clearance below 30 ml/min) or hepatic function is severely impaired, some dosage reduction (approximately by 50%) or extension of the dosage interval should be considered. In conclusion, tramadol is an effective and safe analgesic with a very low interaction potential. Therefore it represents a drug of first choice if moderate to severe pain states have to be treated in pediatric, adult and elderly patients including those with poor cardiopulmonary function.     

Microdialysis for in vivo pharmacokinetic/pharmacodynamic characterization of anti-infective drugs

Inadequate tissue penetration of antibiotics can lead to therapeutic failure and bacterial resistance. Pharmacokinetic evaluation of antibiotics should therefore be based on tissue rather than serum concentrations. Over several years, tissue concentration data obtained by methods such as tissue biopsies have flawed the correct interpretation of antibiotic tissue distribution. Microdialysis--a semi-invasive catheter-based sampling technique--has been employed for the in vivo measurement of antibiotic tissue pharmacokinetics. Owing to selective access to the target site for most anti-infective drugs, microdialysis satisfies regulatory requirements for pharmacokinetic distribution studies and might become a reference technique for tissue distribution studies in the near future. Furthermore, microdialysis might contribute to the definition of meaningful surrogate markers for antibiotic efficiency during drug development.     

Zidovudine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy

Zidovudine (azidothymidine) is a thymidine analogue antiretroviral drug active against human immunodeficiency virus (HIV). In acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) patients, orally and intravenously administered zidovudine is effective in reducing the incidence of opportunistic infections and neoplasms, increasing helper T lymphocyte numbers, and improving survival rates and quality of life. Adverse effects include serious haematological abnormalities and severe headache, abdominal discomfort, nausea, myalgia and insomnia. In addition, neutropenia and other anaemias frequently limit zidovudine therapy and may result in a need for multiple blood transfusions, dose reductions or withdrawal of the drug. However, despite these problems and the lack of information about some aspects of zidovudine use, zidovudine provides a major hope for HIV-infected patients, and it has rapidly become the standard therapy for improving the quality and duration of the lives of AIDS and ARC patients.