Transdermal nicotine: reduction of smoking with minimal abuse liability

Cigarette consumption as well as the physiologic, performance and subjective effects of the nicotine patch were evaluated in ten subjects who smoked ad libitum while residing on a residential research ward for 30 days. Nicotine transdermal systems (patches) delivering a total of 0, 22 or 44 mg per 24 h were applied daily at a constant dose during each 7-day condition; the order of dosing conditions was varied according to a randomized, double-blind, crossover design. Nicotine patches significantly but modestly reduced spontaneous smoking and significantly increased venous plasma nicotine levels. Self ratings of patch liking, satisfaction with cigarettes and the ability to identify the patch condition did not change as a function of the nicotine dose, indicating minimal abuse liability. There were no consistent changes in the puffing pattern measures; however, in all patch conditions, subjects with extensive histories of illicit drug use smoked cigarettes faster than subjects with histories of occasional drug use. Small changes in resting heart rate, pulse and blood pressure occurred when the nicotine patch was worn. Thus large changes in venous plasma nicotine levels engender only modest changes in ad libitum cigarette consumption, measures of abuse liability and cardiovascular effects. These findings are consistent with the notion that the addictive and toxic effects of nicotine are partially determined by the rate of drug administration.     

Physiological pharmacokinetics of a new muscle-relaxant, inaperisone, combined with its pharmacological effect on blood flow rate

This study was designed to develop a physiologically-based pharmacokinetic/pharmacodynamic model for drugs whose pharmacokinetics are influenced by their dose-dependent pharmacological effects. Since blood flow rate is one of the important factors that determine the distribution and elimination processes of drugs, we used inaperisone [IPS, (+/-)-4'-ethyl-2-methyl-3-(1-pyrrolidinyl)-propiophenone hydrochloride], a novel centrally acting muscle relaxant that has been found by us to significantly alter muscle and fat blood flow rates in a dose-dependent manner, as a model compound. With regard to the changes in muscle blood flow rate exhibited by IPS, the brain was shown to be the major site of action based on changes in the observed blood flow rates, determined by the 51Cr-labeled microsphere method, in rats injected iv and intracerebroventricularly with various doses of IPS. Consequently, the blood flow rates in the muscle and fat were well correlated with the concentration of IPS in the brain using Hill's equation. Moreover, hepatic and renal intrinsic clearances of IPS at steady-state were determined by the constant iv infusion method. The saturation of in vivo hepatic and renal metabolisms of IPS was found at venous plasma concentrations higher than 1 microgram/ml. Taken all together, we developed a physiologically-based pharmacokinetic model of IPS combined with its pharmacological effect in rats, which could simulate the concentration-dependent changes in blood flow rates based on the drug concentrations at the site of action.(ABSTRACT TRUNCATED AT 250 WORDS)     

正交设计在维脑路通片工艺改进中的应用

运用正交试验设计和空白颗粒法对维脑路通片制剂工艺进行改进,提高了主药含量,并解决了硬度等方面存在的质量问题。     

Chronopharmacological study of bunazosin hydrochloride in healthy subjects

Bunazosin, an alpha-1 adrenoreceptor blocking agent, was given orally to six healthy subjects in the morning or in the evening in order to examine the time-dependent variations in the pharmacological effects of the drug. The study was carried out on four occasions in a placebo controlled cross-over design. No significant change was observed in blood pressure either after the morning or the evening dosage. Finger skin blood flow (FSBF) assessed by laser Doppler flowmetry increased significantly after the morning dosage, but not after the evening trial. The plasma concentration of bunazosin in the morning in general had a tendency to be greater than that in the evening. A significant correlation was observed between the plasma concentrations and the increments in the FSBF. These results indicate that the pharmacological effects of bunazosin are greater following morning dosage. The present study supports the concept that the time-dependent differences in the effect of bunazosin are, at least, caused by the time-dependent changes in plasma drug concentration.     

Activation of platelets and of fibrinolysis by venous occlusion in healthy volunteers and influence of suloctidil in comparison with placebo

The effect of venous occlusion on blood fibrinolytic activity and platelet activation was studied in 10 normal human volunteers. The procedure was used as a model to study the pharmacological effects of 1-(4-isopropylthiophenyl)-2-n-octylaminopropanol (suloctidil, Sulocton) in a double-blind cross-over trial comparing suloctidil 200 mg three times per day versus identical placebo, each given for one week at random, after an initial one-week placebo run-in; blood sampling was done at the end of each period. Statistically significant changes in plasminogen, alpha 2-anti-plasmin, fibrinogen and antithrombin-III were consistently obtained on each occasion and could be ascribed to local haemoconcentration while a much higher increase of plasminogen activator activity occurred. The influence of venous occlusion on plasma beta-thromboglobulin and platelet factor-4 levels was found to be less consistent and under the trial conditions no obvious difference between the regimens studied could be objectified. On the contrary platelet aggregation by collagen was significantly reduced at the end of the suloctidil period.     

Pharmacokinetics of theophylline in relation to increased pain sensitivity in the rat

In the rat, theophylline increases, in proportion to dose, the sensitivity to painful stimulation. A study of the pharmacological registration of this property combined with the determination of drug levels in plasma indicated that theophylline behaves according to a two-compartment open model. By relating the pharmacological activities to the drug level data using different pharmacokinetic types of calculation, it was concluded that the site of action of theophylline in the central nervous system lies closer to the central (plasma) compartment than to the peripheral one. The registered pharmacological effects of theophylline are thus directly reflected by the plasma concentration of this drug.     

Pharmacokinetics and pharmacodynamics of the antiarrhythmic compound MD750819 in dogs with experimentally induced arrhythmias

Pharmacokinetics and pharmacodynamics were studied in three dogs with interventricular coronary artery ligatures (ligature of Harris) and in three control animals. Weighted nonlinear analysis was used to fit equations describing two and three compartment open models to the experimental data, obtained after intravenous injection (5 mg/kg) of the drug. The three compartment model gave a reduction in the weighted sum of squared residuals and an improvement in the randomness of scatter of the experimental points about the theoretical curve. The postdistribution elimination half-life was longer, the area under the plasma elimination curve larger, and the total body plasma clearance and apparent volume of distribution was reduced in the animals with arrhythmias. The pharmacological response was assessed by recording the ECG and calculating the percentage of normal sinus rhythm/min. A combined pharmacokinetic-pharmacodynamic model was used to analyze data from individual animals. k_e0, a measure of the lag time of pharmacological response behind changes in plasma concentration, and C_e (50), a measure of the sensitivity of the cardiac site of action of the drug, were determined.     

Clinical pharmacology, physiology and pathophysiology of superficial veins--1.

1. Venous resistance contributes very little to total peripheral resistance; more than half of the total blood volume, however, is contained in the extrathoracic veins. Owing to marked differences between venous and arterial anatomy and physiology, studies on veins and arteries usually require different methodological approaches. Whereas for arteries the most relevant parameters are resistance, pressure and flow, for veins volume and compliance are most important. For studies of general aspects of the peripheral circulatory system, venous occlusion plethysmography is probably the most useful method. The determination of both the rate of rise in limb volume and the total volume rise after inflating a proximally applied occlusion cuff to a subdiastolic pressure permits the concomitant estimation of both arterial flow and venous compliance. 2. Studies of direct pharmacological or physiological effects on veins, interactions of various pharmacological or physiological stimuli, or pathophysiological changes in venous responsiveness have been facilitated by the development of investigational techniques relying on direct measurements of the compliance of single human veins in vivo. One of these, relying on the use of a linear variable differential transformer (LVDT) for determining changes in the compliance of superficial veins at a standardized congestion pressure, has been found very suitable for the practical application in both patients and healthy subjects. 3. Physiological studies were carried out on the effect of age, exercise, temperature, and the menstrual cycle on venous compliance and venous responsiveness to various stimuli. In addition, interindividual variability in venous responsiveness in monozygotic and dizygotic twins and in unrelated subjects was investigated, and studies on the function of the endothelium were carried out in man in vivo. 4. Pathophysiological studies using this technique were reported from patients with hypertension, orthostatic hypotension, myocardial infarction, varicosis, cystic fibrosis, asthma, diabetes, systemic sclerosis, and cluster headache. 5. Clinical pharmacological studies represent a most important field for the use of this method. Studies were carried out on the effects of a large number of constrictor and dilator agents, and also on drug interactions on human veins in vivo. Venoconstriction was observed after local administration of alpha-adrenoceptor and 5-HT-receptor agonists, ergot derivatives, angiotensinogen, angiotensin I and II, and several prostaglandins. 6. Owing to the low venous tone present under effects can usually be quantified only on veins e.g. noradrenaline or 5-hydroxytryptamine. Under these conditions dilatation was observed after the administration of beta-adrenoceptor agonists, cholinergic (muscarinic) agonists, nitrates, calcium antagonists, bradykinin, substance P and several prostaglandins.     

Pharmacokinetic drug interactions with amiodarone

Amiodarone alters the pharmacokinetics, and in some cases the pharmacodynamics, of several clinically important drugs. The major mechanisms of its drug interactions is inhibition of hepatic metabolism, but it can also affect the bioavailability, protein binding and renal excretion of coadministered drugs. It significantly increases the plasma concentrations of digoxin, warfarin, many Class I antiarrhythmic drugs (quinidine, procainamide, aprindine and flecainide) and phenytoin, in some instances resulting in overt signs of clinical toxicity, including adverse cardiovascular, cardiac and central nervous system effects. In most cases 20 to 50% reductions in doses of the affected drugs are necessary to offset the pharmacokinetic alterations and increased plasma drug concentrations caused by amiodarone. Interactions between amiodarone and beta-blockers (e.g. propranolol) and calcium channel blockers (e.g. diltiazem) are associated more with electrophysiological (sinus bradycardia and sinus arrest) and/or haemodynamic toxicity, due to additive pharmacological effects, than to changes in pharmacokinetics. In patients undergoing surgical procedures amiodarone interacts with general and local anaesthetic agents, resulting in an increased risk of cardiac system complications including hypotension and bradycardia. There is still a need for prospective controlled clinical studies to be conducted on many likely combinations of other drugs with amiodarone to increase understanding of the magnitude, time-course, mechanism and relevance of pharmacokinetic changes caused by this drug.     

Pharmacokinetic and pharmacodynamic considerations when treating patients with sepsis and septic shock

Sepsis and septic shock are accompanied by profound changes in the organism that may alter both the pharmacokinetics and the pharmacodynamics of drugs. This review elaborates on the mechanisms by which sepsis-induced pathophysiological changes may influence pharmacological processes. Drug absorption following intramuscular, subcutaneous, transdermal and oral administration may be reduced due to a decreased perfusion of muscles, skin and splanchnic organs. Compromised tissue perfusion may also affect drug distribution, resulting in a decrease of distribution volume. On the other hand, the increase in capillary permeability and interstitial oedema during sepsis and septic shock may enhance drug distribution. Changes in plasma protein binding, body water, tissue mass and pH may also affect drug distribution. For basic drugs that are bound to the acute phase reactant alpha(1)-acid glycoprotein, the increase in plasma concentration of this protein will result in a decreased distribution volume. The opposite may be observed for drugs that are extensively bound to albumin, as the latter protein decreases during septic conditions. For many drugs, the liver is the main organ for metabolism. The determinants of hepatic clearance of drugs are liver blood flow, drug binding in plasma and the activity of the metabolic enzymes; each of these may be influenced by sepsis and septic shock. For high extraction drugs, clearance is mainly flow-dependent, and sepsis-induced liver hypoperfusion may result in a decreased clearance. For low extraction drugs, clearance is determined by the degree of plasma binding and the activity of the metabolic enzymes. Oxidative metabolism via the cytochrome P450 enzyme system is an important clearance mechanism for many drugs, and has been shown to be markedly affected in septic conditions, resulting in decreased drug clearance. The kidneys are an important excretion pathway for many drugs. Renal failure, which often accompanies sepsis and septic shock, will result in accumulation of both parent drug and its metabolites. Changes in drug effect during septic conditions may theoretically result from changes in pharmacodynamics due to changes in the affinity of the receptor for the drug or alterations in the intrinsic activity at the receptor. The lack of valid pharmacological studies in patients with sepsis and septic shock makes drug administration in these patients a difficult challenge. The patient's underlying pathophysiological condition may guide individual dosage selection, which may be guided by measuring plasma concentration or drug effect.     

Modeling the acute pharmacological response to selective serotonin reuptake inhibitors in human brain using simultaneous PET/MR imaging

Pharmacological imaging of the effects of selective serotonin reuptake inhibitors (SSRI) may aid the clarification of their mechanism of action and influence treatment of highly prevalent neuropsychiatric conditions if the detected effects could be related to patient outcomes. In a randomized double-blind design, 38 healthy participants received a constant infusion of 8 mg citalopram or saline during either their first or second of two PET/MR scans. Resting-state functional MRI (fMRI) was acquired simultaneously with PET data on the binding of serotonin transporters (5-HTT) using [¹¹C]DASB. Three different approaches for modeling of pharmacological fMRI response were tested separately. These relied on the use of regressors corresponding to (1) the drug infusion paradigm, (2) time courses of citalopram plasma concentrations and (3) changes in 5-HTT binding measured in each individual, respectively. Furthermore, the replication of results of a widely used model-free analysis method was attempted which assesses the deviation of signal in discrete time bins of fMRI data acquired after start of drug infusion. Following drug challenge, average 5-HTT occupancy was 69±7% and peak citalopram plasma levels were 111.8 ± 21.1 ng/ml. None of the applied methods could detect significant differences in the pharmacological response between SSRI and placebo scans. The failed replication of SSRI effects reported in the literature despite a threefold larger sample size highlights the importance of appropriate correction for family-wise error in order to avoid spurious results in pharmacological imaging. This calls for the development of analysis methods which take regional specialization and the dynamics of brain activity into account.     

Peripheral hemodynamic and humoral effects of oral zofenopril calcium (SQ. 26,991) in patients with congestive heart failure

In 14 patients with congestive heart failure (CHF) of various grade (NYHA class 2-4) the effects of zofenopril calcium (SQ 26,991) on blood pressure and forearm circulation were studied by venous occlusion plethysmography. Changes in plasma renin activity (PRA), aldosterone, Atrial natriuretic factor (ANF) and arginine-vasopressin (AVP) were also measured. Two hours after oral administration of 7.5 mg of zofenopril we observed a decrease in blood pressure, heart rate, and forearm vascular resistance along with an increase in venous distensibility. Zofenopril also decreased ANP levels in a manner directly related to peripheral venodilatation (r = .64; P less than .05) and modified arginine-vasopressin (AVP) proportionally to the fall in blood pressure observed in response to drug administration (%SBP/%AVP: r = .64, P less than .05; %DBP/%AVP: r = .67, P less than .05). Hemodynamic and humoral responses to zofenopril occurred without any significant unwanted adverse reaction, even in patients with greater pressor reduction. We conclude that oral acute zofenopril administration, in patients with congestive heart failure, causes an arterial and venous forearm vasodilatation which is probably involved in the acute changes in plasma levels of ANF and AVP observed after drug administration.     

Relationship between dose,blood level and haemodynamic response in patients with cirrhosis receiving propranolol

Summary Fifty-two patients with cirrhosis receiving continuous administration of propranolol in doses reducing the heart rate by 25% were studied. The doses and plasma levels varied widely — 185±98 mg/day (mean ± SD) and 208±153 ng/ml, respectively. These values were significantly correlated. No significant correlation was found between the dose of the drug or plasma level and the liver function tests. Although propranolol significantly decreased cardiac output and the hepatic venous pressure gradient, no correlation was found between drug dose or plasma level and these haemodynamic effects.     

Impact of genetic polymorphisms of transporters on the pharmacokinetic, pharmacodynamic and toxicological properties of anionic drugs

As the importance of drug transporters in the clinical pharmacokinetics of drugs is recognized, genetic polymorphisms of drug transporters have emerged as one of the determinant factors to produce the inter-individual variability of pharmacokinetics. Many clinical studies have shown the influence of genetic polymorphisms of drug transporters on the pharmacokinetics and subsequent pharmacological and toxicological effects of drugs. The functional change in a transporter in clearance organs such as liver and kidney affects the drug concentration in the blood circulation, while that in the pharmacological or toxicological target can alter the local concentration at the target sites without changing its plasma concentration. As for the transporters for organic anions, some single nucleotide polymorphisms (SNPs) or haplotypes occurring with high frequency in organic anion transporting polypeptide (OATP) 1B1, multidrug resistance 1 (MDR1), and breast cancer resistance protein (BCRP) have been extensively investigated in both human clinical studies and in vitro functional assays. We introduce some examples showing the relationship between haplotypes in transporters and pharmacokinetics and pharmacological effects of drugs. We also discuss how to predict the effect of functional changes in drug transporters caused by genetic polymorphisms on the pharmacokinetics of drugs from in vitro data.     

The phenomenon and rationale of marked dependence of drug concentration on blood sampling site. Implications in pharmacokinetics, pharmacodynamics, toxicology and therapeutics (Part I)

At least 42 compounds have been reported to exhibit significant or marked blood sampling site dependence in concentration after dosing in humans and animals. The very high efficiency of uptake of drug by the poorly perfused sampling tissue (e.g. arm or leg) during its very short transit through the capillary (1 to 3 seconds) is mainly responsible for such a universal phenomenon. When marked arteriovenous concentration differences exist, their entire plasma (blood or serum) concentration-time profiles may resemble those obtained from completely different drugs or from different dosing rates. After an intravenous bolus injection, the reported maximal arteriovenous differences were 3240-fold for griseofulvin during the early distribution phase (arterial concentration being higher than venous, and 234% for procainamide during the terminal phase (venous concentration being higher). The reported maximal steady-state arteriovenous difference during infusion was 3.8-fold for glyceryl trinitrate (nitroglycerin), with the arterial level higher, due to metabolism and possible strong binding by sampling tissue. Interestingly, peak arterial plasma concentrations were usually achieved at about 0.5 minutes, while peak venous plasma concentrations generally occurred at 1 to 5 minutes after injection. Thus, the plasma concentration-time profile after an intravenous bolus injection actually resembles that predicted for a short term intravenous infusion, according to the classical instantaneous input hypothesis. Potential factors that may affect the degree of arteriovenous difference are here reviewed in detail. The implications of potential marked arteriovenous differences in pharmacokinetics, in pharmacokinetic/pharmacodynamic correlations or modelling, in toxicology, and in drug therapy are extensively discussed. Clinicians or scientists dealing with the determination and/or use of plasma concentration data should be fully aware of this problem. Many previous studies, based on the commonly accepted assumption that immediately or shortly after dosing plasma (blood) concentrations are essentially uniform throughout the blood circulation or the central (plasma) compartment, may require a reexamination. This is particularly important since the 'driving force' for distribution of a drug to various parts of the body for elimination, for accumulation or for producing a pharmacological or toxic effect, is its concentration in arterial blood, and not in venous blood drained from a poorly perfused tissue (venous blood may more accurately reflect drug concentrations in the poorly perfused sampling tissue itself). The present review probably represents the first of its kind ever reported in the literature. It is hoped that the review will increase the awareness of this very fundamental and important subject matter among our readers, and may also stimulate further studies or discussions.     

Predicting brain concentrations of drug using positron emission tomography and venous input: modeling of arterial-venous concentration differences

Objective In a positron emission tomography (PET) study, the concentrations of the labeled drug (radiotracer) are often different in arterial and venous plasma, especially immediately following administration. In a PET study, the transfer of the drug from plasma to brain is usually described using arterial plasma concentrations, whereas venous sampling is standard in clinical pharmacokinetic studies of new drug candidates. The purpose of the study was to demonstrate the modeling of brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform (T_av).Methods Brain kinetics (C_br) was described as the convolution of arterial plasma kinetics (C_ar) with an arterial-to-brain impulse response function (T_br). The arterial plasma kinetics was obtained as venous plasma kinetics (C_ve) convolved with the inverse of the arterio-venous transform (T_av ⁻¹). The brain kinetics was then given by C_br=C_ve*T_av ⁻¹*T_br. This concept was applied on data from a clinical PET study in which both arterial and venous plasma sampling was done in parallel to PET measurement of brain drug kinetics. The predictions of the brain kinetics based on an arterial input were compared with predictions using a venous input with and without an arterio-venous transform.Results The venous based models for brain distribution, including a biexponential arterio-venous transform, performed comparably to models based on arterial data and better than venous based models without the transform. It was also shown that three different brain regions with different shaped concentration curves could be modeled with a common arterio-venous transform together with an individual brain distribution model.Conclusion We demonstrated the feasibility of modeling brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform. Such a model can in turn be used for the calculation of brain kinetics resulting from an arbitrary administration mode by applying this model on venous plasma pharmacokinetics. This would be an important advantage in the development of drugs acting in the brain, and in other circumstances when the effect is likely to be closer related to the brain than the plasma concentration.     

Phenytoin and phenobarbital assayed by the ACCULEVEL method compared with EMIT in an outpatient clinic setting

The ACCULEVEL (Syntex) therapeutic drug assay technique was evaluated for phenytoin and phenobarbital in 30 patients with epilepsy who attended a neurology outpatient clinic. This finger-prick whole blood method is calibrated by the manufacturer to give assay results equivalent to plasma drug concentration. The results were compared with EMIT (Syva) technique measurements on the plasma from venous blood drawn simultaneously. The results presented show regression lines of y = 0.91x + 10.8, (r2 = 0.92) and y = 0.97x + 5.01, (r2 = 0.77) for phenytoin and phenobarbital (microM), respectively, when the ACCULEVEL finger-prick blood assay was compared with the EMIT venous plasma assay. Acceptable precision and accuracy data are presented for replicated ACCULEVEL assays. The ACCULEVEL method was found to be reliable when performed by a laboratory technician and provides a very convenient quantitative drug assay that could easily be performed by a variety of individuals at a site remote from laboratory facilities.     

Ultrafiltration as a fast and simple method for determination of free and protein bound prilocaine concentration. Clinical study following high-dose plexus anesthesia

Ultrafiltration as a Fast and Simple Method to Separate Free and Protein Bound Concentrations of Local Anesthetics/Pharmacokinetic studies following high-dose anesthesia of the axillary plexus. As many other drugs amide-type local anesthetics are protein bound in plasma. The extent of binding varies between local anesthetics. The free, non protein-bound fraction of these drugs is mainly responsible for cardiovascular and central-nervous side effects. If high doses are necessary for regional anesthetic procedures it seems reasonable to determine the pharmacological active, non protein-bound fraction in addition to the total concentration of the local anesthetic drug. Analyses of protein binding was performed using an ultrafiltration method which is discussed in this paper. Total (HPLC) and unbound plasma levels (combination of ultrafiltration and HPLC) of the local anesthetic drug in central venous blood were studied in 20 healthy orthopedic patients, undergoing plastic surgery of the upper limb (elbow, forearm, hand), over a time period of 90 min, when performing axillary plexus block with 30 ml prilocaine (CAS 721-50-6) 2% (= 600 mg). Separation of the local anesthetic fractions was achieved using the ultrafiltration system MPS-1, equipped with a YMT-membrane. These membranes have a narrow pore size retaining molecules larger than 30000 Dalton. Ultrafiltration was accomplished by subjecting 1.2 ml of plasma to centrifugation at 2000 x g for 60 min at 30 degrees C using a clinical centrifuge equipped with a 35 degree angle head rotor. The plasma samples were adjusted to physiological pH (7.40) with a sodium-potassium-phosphate buffer. The tightness of the used membrane was controlled by a micromethod for protein estimation (sensitivity 10 micrograms/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

An integrated microdialysis rat model for multiple pharmacokinetic/pharmacodynamic investigations of serotonergic agents

INTRODUCTION: Integrated in vivo models applying intracerebral microdialysis in conjunction with automated serial blood sampling in conscious, freely moving rodents are an attractive approach for pharmacokinetic (PK) and simultaneous pharmacokinetic/pharmacodynamic (PK/PD) investigations of CNS active drugs within the same animal. In this work, the ability to obtain and correlate data in this manner was evaluated for the selective serotonin (5-HT) reuptake inhibitor (SSRI) escitalopram. METHODS: An instrumented rat model equipped with an intracerebral hippocampal microdialysis probe and indwelling arterial and venous catheters was applied in the studies. Concomitant with brain microdialysis, serial blood sampling was conducted by means of an automated blood sampling device. The feasibility of the rat model for simultaneous PK/PD investigations was examined by monitoring plasma and brain extracellular concentrations of escitalopram along with SSRI-associated pharmacological activity, monitored as changes in brain 5-HT levels and plasma corticosterone levels. RESULTS: Combining intracerebral microdialysis and automated blood sampling did not cause any detectable physiological changes with respect to basal levels of plasma corticosterone or brain 5-HT levels. Furthermore, the PK of escitalopram in hippocampus following intravenous injection was not influenced by the presence of vascular catheters. Conversion of escitalopram dialysate concentrations into absolute extracellular levels by means of in vivo retrodialysis was verified by the no-net-flux method, which gave similar recovery estimates. The PK of escitalopram could be characterized simultaneously in plasma and the hippocampus of conscious, freely moving rats. Concomitantly, the modulatory and functional effects of escitalopram could be monitored as increases in brain 5-HT and plasma corticosterone levels following drug administration. DISCUSSION: The applicability of intracerebral microdialysis combined with arterial blood sampling was demonstrated for simultaneous PK/PD investigations of escitalopram in individual rats under non-stressful conditions. Together, these temporal relationships provide multiple PK/PD information in individual animals, hence minimizing inter-animal variation using a reduced number of animals.     

Protein binding displacement interactions and their clinical importance

The binding of drugs to proteins is an important pharmacokinetic parameter. Many methods are available for the study of drug protein binding phenomena and there are also many ways to interpret the binding data. Although much emphasis has been placed on the binding of drugs in the plasma, binding also takes place in the tissues. Displacement interactions involving plasma or tissue binding sites have been implicated as the causative mechanisms in many drug interactions. However, the importance of plasma binding displacement as a mechanism of drug interactions. However, the importance of plasma binding displacement as a mechanism of drug interaction has been overestimated and overstated, being based largely on in vitro data. Because displaced drug can normally distribute out of the plasma compartment, increases of free drug concentrations are usually transient and therefore will not give rise to changed pharmacological effects in the patient. Those clinically important drug interactions formerly considered to be caused via displacement from plasma binding sites usually have another interaction mechanism involved; commonly decreased metabolism or renal elimination also takes place. Plasma binding displacement interactions, however, do become important clinically in certain specific situations, namely, when the displacing drug is administered quickly to the patient by the intravenous route, during therapeutic drug monitoring, and in certain drug disposition studies which involve the use of a heparin lock for blood sampling. Tissue binding displacement interactions have a greater potential to cause adverse effects in the patient as in this case drug will be forced from extravascular sites back into the plasma. The resulting increased drug plasma levels will lead to enhanced pharmacological effects and, possibly, frank toxicity. Displacement of drugs from binding sites simultaneously in both the plasma and in the tissues will combine the effects seen after displacement from the separate areas. Due to decreased binding in both areas, the free drug concentration in the plasma will increase leading to overactivity of the displaced drug.