Experimental and Clinical Pharmacokinetics of Fluoxetine and Amitriptyline: Comparative Analysis and Possible Methods of Extrapolation.

The pharmacokinetics of two fluoxetine capsulated dosage forms and two amitriptyline tablet forms after a single oral intake was studied in dogs and healthy volunteers. High significant correlations were detected between plasma concentrations of fluoxetine (r=0.96, p<0.00001, n=11) and amitriptyline (r=0.78, p<0.0224, n=8) in dogs and volunteers. A correlation of medium strength (though insignificant) was detected between nortriptyline concentrations in the plasma of dogs and volunteers (r=0.69, p<0.199, n=5). The bioavailability parameters of the test drugs in dogs and volunteers did not differ. Similar trends of fluoxetine and amitriptyline pharmacokinetic parameters were revealed in volunteers and animals. Methods for extrapolation of experimental pharmacokinetics parameters of fluoxetine and amitriptyline obtained on dogs for humans are proposed and validated.

Experimental and clinical pharmacokinetics of amitryptiline: comparative analysis.

Pharmacokinetics of two amitriptyline tablets, Amitryptiline Nycomed and Amitryptiline, was investigated clinically and experimentally after a single oral dose of 50 mg. A statistically significant correlation between amitryptiline serum concentrations in dogs and healthy humans (r=0.683, p<0.006) was established. In humans, standartized values of peak concentration and area under the concentration curve were significantly higher, specific volume of distribution and total clearance were lower, and half-life and mean retention time were significantly higher than in dogs. Characteristics of apparent bioavailability in dogs and healthy people did not statistically differ.

[The binding of drugs with erythrocytes]. / Sviazyvanie lekarstvennykh sredstv s éritrotsitami.

The article reviews the data on the binding of drugs to erythrocytes. Various mechanisms of the uptake of drugs by the erythrocytes and the role of the red blood cells as carriers of the drugs to the target organs are discussed. Significant correlation of the clinical and pharmacological effect of many drugs with their content in the erythrocytes is shown. Determination of the pharmacological parameters from the content of the drugs in the erythrocytes or whole blood rather than in the plasma is recommended.

[Verapamil binding with the blood erythrocytes and cardiac output in myocardial infarct patients]. / Sviazyvanie verapamila s éritrotsitami krovi i serdechnyi vybros u bol'nykh infarktom miokarda.

In 14 patients with myocardial infarction the degree of verapamil binding with blood erythrocytes after a single oral administration (80 mg/kg) and the dependence pharmacological effect, the minute heart output (+ % MOC), on verapamil content in plasma and erythrocytes were studied. Intraindividual variability of verapamil distribution coefficients between erythrocytes and plasma (RBC/Ptot) is 9.7 +/- 2,3%, and it differs reliably from values of inter-individual variability of this index (33.7 +/- 3.3%).

[The pharmacokinetic and pharmacodynamic characteristics of foridon during interaction with the metabolic oxidation inhibitor dopegit]. / Osobennosti farmakokinetiki i farmakodinamiki foridona pri vzaimodeistvii s ingibitorom metabolicheskogo okisleniia dopegitom.

The paper deals with some aspects of the effects produced by dopegite on the pharmacokinetics and pharmacodynamics of foridone from a group of calcium antagonists. Nineteen patients with essential hypertension received a single doses of foridone of 40 mg, then its course therapy in a dose of 90 mg/day for 2 weeks, then it was supplemented with dopegite in a dose of 750 mg/day for 2 weeks too. Supplementation of dopegite caused statistically significant changes as higher plasma concentrations of foridone and increased concentration-time curve areas, decreased total peripheral resistance and regional, and a lower spasm index. Dopegite can be used to enhance the antihypertensive effect of foridone.

[Acebutolol and diacetolol: their binding to plasma proteins and erythrocytes and secretion with the saliva]. / Atsebutolol i diatsetolol: sviaz' s belkami plazmy i éritrotsitami, sekretsiia so sliunoi.

Thirty-two patients with hypertensive disease were treated with a cardioselective blocker of beta-adrenergic receptors acebutolol ("Sectral-400", Rhone Poulenc, France). The binding of the drug and its metabolites diacetolol to plasma proteins and erythrocytes and their excretion with the saliva were studied. The significant binding of acebutolol and diacetolol to erythrocytes was shown. The ratio of the content of the free form of these substances in erythrocytes to plasma content was on the average 1.54 +/- 0.96 for diacetolol and 1.93 +/- 1.01 for acebutolol. A good correlation of acebutolol and diacetolol contents in the saliva with their contents in plasma was found. The mean values of the protein-bound fraction were for acebutolol 0.133 +/- 0.038 and for diacetolol 0.106 +/- 0.050.

[Propranolol binding with plasma proteins and erythrocytes]. / Sviaz' propranolola s belkami plazmy i eritrotsitami.

The binding of propranolol with plasma proteins and erythrocytes after oral administration of 80 mg of anapriline was studied in 12 patients with hypertensive disease. The content of propranolol fraction bound to plasma proteins was on the average 0.84 +/- 0.4. It was shown that propranolol to a considerable degree is captured by erythrocytes. The ratios of the erythrocyte content of propranolol free form to the plasma content were on the average 3.72 +/- 0.92 and 2.70 +/- 1.20, respectively, 2 and 4 hours after anapriline intake. During the assessment of the pharmacological parameters it is recommended to determine the contents of the total and free forms of propranolol in the whole blood rather than in plasma.

[A comparative study of the pharmacokinetics of oral preparations of theophylline]. / Sravnitel'noe izuchenie farmakokinetiki peroral'nykh preparatov teofillina.

The pharmacokinetics of five preparations of theophylline--euphylline and sustained-release forms (theo-dura, retaphylline, theopac and theobilong) was studied in 50 patients with the broncho-obstructive syndrome. Blood serum theophylline concentration was determined by high performance liquid chromatography. The main differences in the pharmacokinetic parameters manifested themselves in the period of half-absorption--the least one for euphylline and the greatest one for theopac. A close correlation between blood serum theophylline concentration and the profile of theophylline release from theopac tablets was revealed. The equal theophylline concentration in blood serum was determined on the 4th and 7th days of the course treatment with sustained-release preparations administered twice a day, the concentration values ranged within the subtherapeutic level. An increase of the dose by 50-150 mg/day resulted in an increase of blood serum theophylline concentration within the therapeutic range.

[Ethmozine pharmacokinetics in liver insufficiency]. / Farmakokinetika étmozina pri nedostatochnosti funktsii pecheni.

The authors' findings permit a conclusion that the risk of ethmozine overdosage leading to undesirable side effects (dryness in the mouth, noise in the ears, a 'net' in eyes; giddiness, nausea, vomiting) is very high when routine ethmozine doses are administered to patients with grave (Stages II-III) impairments of liver function; this is explained by (1) reduced rate of ethmozine biotransformation, this resulting in a heightened concentration of the drug in the blood, and (2) by an increase of the drug free fraction concentration due to its reduced ability to bind with the blood plasma proteins. This necessitates a pharmacokinetic monitoring of such patients prescribed ethmozine and a correction of the drug dose, if necessary.

[The clinical pharmacology and efficacy of the new Soviet calcium antagonist foridon]. / Klinicheskaia farmakologiia i éffektivnost' novogo otechestvennogo antagonista kal'tsiia foridona.

A total of 56 patients with coronary heart disease (CHD), angina pectoris of effort, functional classes II-III, were placed under observation. All the patients received 20 mg foridon (F), 20 mg corinfar (C), 80 mg anapriline (A). 24 patients were subjected to the continuous treatment with F (20 mg 4 times a day). The antianginal action of the drug was compared to the blood concentration on days 7, 14, 21, 28, 43 and 57 of the treatment with F. In 14 patients with angina pectoris and in 18 patients with essential hypertension, the efficacy of F and C was cross correlated. It has been demonstrated that F can be successfully used for the treatment of patients with CHD, angina pectoris of effort and (or) essential hypertension. The increase of the single dose of foridon from 20 to 40 mg does not result in the potentiation of its hypotensive effect. F and C provoke the highest rise of exercise tolerance with combined angina pectoris. Continuous concomitant administration of F and C with A leads to the potentiation of the antianginal action.

[Pharmacokinetic characteristics of ethacizine in patients with disorders of heart rhythm]. / Osobennosti farmakokinetiki étatsizina u bol'nykh s narusheniiami ritma serdechnoi deiatel'nosti.

Significant differences in values of the volume of ethacizine distribution and clearance at oral administration in patients with myocardial infarction from those in patients with other pathology were established. A considerable decrease of ethacizine bioavailability in myocardial infarction patients was shown.

[Pharmacokinetic research on theophylline]. / Issledovanie farmakokinetiki teofillina.

Blood serum theophylline concentrations were studied in 6 volunteers and 8 patients with bronchospastic syndrome by using an enzyme immunological assay with a commercial kit "Fedesim" (USA) at intravenous and oral administration of euphylline in a dose of 5 mg/kg. The maximal concentration at intravenous injection of euphylline was reached in volunteers in 15 minutes, at oral administration--in 90 minutes, and in patients--somewhat later.

[Comparison of the results of ethacizin pharmacodynamics and pharmacokinetics in a single intravenous administration]. / Sopostavlenie rezul'tatov farmakodinamiki i farmakokinetiki étatsizina pri razovom vnutrivennom vvedenii.

A single intravenous injection of 30-50 mg ethacizin produces a favourable antiarrhythmic effect in 80-85% of patients with ventricular disorders of cardiac rhythm. The drug's action already begins "on the needle", reaches its peak within 3-5 minutes and lasts for 1-2 hours. A two-compartment model adequately represents ethacizin pharmacokinetics. The average ethacizin half-distribution and half-elimination periods are 4.7 and 154.4 minutes, respectively, and its clearance rate is 0.99 1/min. Therapeutic plasma concentration of the drug varies between 30-50 and 300-400 ng/ml.

[Pharmacokinetics of the new Soviet anti-arrhythmia preparation etacizin]. / Farmakokinetika novogo otechestvennogo antiarutmicheskogo preparata étatsizina.

Ten patients without marked abnormalities on the part of the liver and kidneys were examined for the pharmacokinetics of a new Soviet antiarrhythmic drug etacizin. The drug was injected intravenously at a rate of 0.5-0.8 mg/kg bw. The blood required for determining drug concentrations was taken 1, 2, 3 and 4 hours after drug jet injection. It was demonstrated that the drug half-life was on the average 164 +/- 24.7 min, exceeding 2 times the half-life of etmozine, a drug of the same series applied to the treatment of some forms of heart rhythm abnormalities.

[Pharmacokinetic characteristics of lidocaine in patients with circulatory failure]. / Osobennosti farmakokinetiki lidokaina u bol'nykh s nedostatochnost'iu krovoobrashcheniia.

It has been shown with special reference to 35 patients suffering from myocardial infarction, atherosclerotic cardiosclerosis and rheumatic heart diseases associated with varying degrees of circulatory insufficiency that the final amount of distribution and halflife of lidocaine directly correlated with the cardiac index. A formula has been suggested for calculating the amount of distribution of the drug on the basis of the cardiac index. It has been demonstrated that the formula can be used for the development of therapeutically effective lidocaine concentration in the patients' blood.