Bioequivalence of allopurinol-containing tablet preparations.

AIM: The study was undertaken to prove the bioequivalence of two allopurinol tablet preparations. SUBJECTS, MATERIALS AND METHODS: The relative bioavailability of allopurinol from two tablet preparations (Uribenz vs. Zyloric 300) was estimated on 18 volunteers of both sexes in an open randomized study by administering one tablet of each preparation at an interval of 2 weeks. The plasma concentrations of allopurinol and its active metabolite oxypurinol were measured over a time-period of 72h by HPLC. RESULTS: While the mean AUC(0-72) values of allopurinol and oxypurinol after the test and reference preparations are entirely identical (5.33 vs. 5.21 and 137.95 vs. 137.96 microg h ml(-1), respectively), the C(max) values of oxypurinol unlike those of allopurinol show small differences (4.59 vs. 4.78 and 1.91 vs. 193 microg/ml, respectively). According to the parametric and non-parametric analysis, the quotients AUC(T)/AUC(R) and C(maxT)/C(maxR) lie within the confidence intervals 0.8 to 1.2 and 0.7 to 1.3 respectively With regard to the t(max) of allopurinol, the differences of test and reference preparations are between 0.10 to 0.05h and of oxypurinol between -0.10 to 0.87h (parametric analysis). Both, Uribenz 300 and Zyloric 300 caused a maximum decrease of the uric acid concentration in the volunteers by 18% after 10 and 24h, respectively. CONCLUSION: Thus the bioequivalence of the allopurinol tablet preparations is demonstrated.

Bioequivalence of tolbutamide-containing tablet preparations.

The present crossover study was undertaken to investigate in 22 volunteers (15 males, 7 females, aged 22-28 years) whether the 2 tolbutamide preparations (tolbutamide R.A.N. vs. rastinon Hoechst) are bioequivalent. After administering a single dose of one 1 g tablet of each preparation the plasma tolbutamide concentration was measured by HPLC over a time-period of 48 hours. The mean AUC0-48 values are nearly identical (998.42 vs. 997.73 micrograms x h x ml-1), while the Cmax values (51.1 vs. 58.8 micrograms/ml) and the tmax values (4.55 vs. 3.82 h) show slight differences. The Westlake intervals claimed to prove bioequivalence lies in the 95% confidence interval between the limits 0.972 and 1.046 (AUC), 0.896 and 0.978 (Cmax), and 0.056 and 1.346 (tmax). For example, this is the result of the parametric analysis considering the randomization. In the case of the parameters of the multiplicative model (AUC and Cmax) the probability of correctly concluding bioequivalence (power) between the 2 preparations reaches 2.0. Regarding maintenance therapy it is of minor importance that the maximum plasma tolbutamide concentrations is 0.7 h later observed with the test preparation than with the standard. The results of this study allow the conclusion that the 2 tablet preparations are bioequivalent.

Absorption and bioavailability of pentaerithrityl-tetranitrate (PETN, Dilcoran 80).

The effects of 80 mg pentaerithrityl-tetranitrate (PETN) as suspension or formulated as tablets were compared to placebo in a single blind, randomized, crossover study in 18 healthy subjects (study A), and the bioequivalence of two tablet formulations (marketed Dilcoran 80 vs a new formulation) was studied in 24 healthy subjects after administration of single oral doses of 80 mg PETN according to a placebo controlled, randomized, double blind, two-way crossover study design (study B). The perfusion of the right middle finger was measured by rheography (altitude A of the changes of resistance and of the incisure D) before and 24 h post-dose, and blood pressure and heart rate were measured in supine position at the same time. The values of area under curve (AUC) of the ratio A/D were calculated by the trapezoidal rule. In study A the mean A/D-values were reduced from about 2.0 to about 1.3 after intake of PETN (solution or tablet) with a minimum 60 to 90 min postdose (solution) and 2 h postdose (tablet). A significant reduction in this ratio was seen up to 8 (solution) or 12 h (tablet) post dose. Changes in blood pressure were not observed while the heart rate decreased in the subjects of all three groups 1 to 2 h postdose followed by an increase by 6 to 10 beats per min. After subtraction of the AUC values of placebo from the PETN-derived AUC values, mean values of 6.61 (SD 1.52, solution) and 7.25 (SD 1.48, A/D*h, tablet) were calculated (p > 0.1, study A).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of phenprocoumon.

The pharmacokinetics of phenprocoumon was studied in 24 healthy volunteers between the ages of 23 and 28 years and a mean body weight of 72 kg by intraindividual comparison of the plasma level after i.v. and oral administration of 9 mg phenprocoumon (PPC) or by the evaluation of the total plasma clearance of PPC by simultaneous measurement of the urinary excretion and of the plasma concentration after the administration of 9 mg PPC. The following mean data were obtained after i.v. injection:t1/2 alpha 0.432h, t1/2 beta 128 h, co 0.651 microgram/ml, Vd 14.41,AUCo-omega 121 micrograms x h/ml. After intake of 9 mg PPC the following mean values were measured: tmax 2.25 h, Cmax 1.01 micrograms/ml, tabs 0.553 h, co 0.865 micrograms/ml, t1/2 beta 132 h, AUC0-infinity 164 micrograms x h/ml. By comparison of the PPC plasma level with the corresponding urinary excretion, a total mean PPC clearance of 20.0 (i.v.) and 15.1 (per os) ml/h was calculated within the first 8 h post dose, while the values measured did not differ between 8 and 48 h post dose (14.8 vs 15.3 ml/h). The steep decline in plasma level after i.v. injection of PPC might be caused by an enhanced renal and hepatic elimination of the free drug to a higher degree than after oral intake, while no differences existed between both modes of administration during the phase of elimination. A nearly total absorption of PPC from the tablet formulation is suggested.

[The diagnostic value of the aminophenazone breath test in chronic liver diseases]. / Untersuchungen zum diagnostischen Stellenwert des Aminophenazon-Atemtestes bei chronischen Lebererkrankungen.

In 230 patients (90 females, 140 males aged between 20 and 73 years, average age 47.8 years) with and without exception histologically and/or laparoscopically ascertained chronic liver diseases (degenerative damages of liver parenchyma in 45, fatty liver stage I in 28, fatty liver stage II in 36, cholangiohepatitis in 4, chronic persisting hepatitis in 31, chronic active hepatitis in 57 and liver cirrhosis in 59 cases) the incorporation of the aminophenazon breathing test in the so-called laboratory chemical liver spectrum was controlled. The restriction of the microsomal biotransformation established by means of the aminophenazon breathing test behaved parallel to the degree of severity of the disease. The aminophenazon breathing test was performed in the modification after Haustein and Schenker (1985). The largest delays in the decomposition were found in the complete cirrhotic transformation of the liver. The unequivocally pathologic result of the aminophenazon breathing test in severe irreversible damages of the liver parenchyma was confirmed by the formation of correlations with parameters of the conventional laboratory spectrum of the liver. Thus the restriction of the performance of the synthesis of the liver for coagulation factors and albumins was parallel to the loss of function of the mixed functional oxidases. In all patients with chronic liver diseases a connection between the value of the thromboplastin time (Quick's test) and result of the breathing test was found. Positive linear correlation between serum albumin and results of the breathing test could also be proved particularly in the group of the severe chronic inflammatory liver diseases. In chronic fibrosing liver diseases there were positive inverse correlations between gamma-globulin concentration in the serum and thymol turbidity test on the one hand as well as the aminophenazon breathing test on the other. There were no correlations between liver enzyme and aminophenazon breathing test. The results of the own investigations incorporate the aminophenazon breathing test as indicator of a severe liver cell damage which at the same time is established by the pathological result of the so-called synthesis parameters of the liver.

[Studies on diagnostic and prognostic validity of aminophenazone breath test in liver cirrhosis]. / Untersuchungen der diagnostischen und prognostischen Wertigkeit des Aminophenazon-Atemtestes bei Leberzirrhose.

In 59 patients with liver cirrhosis (23 female, 36 male; aged between 30 and 73 years) the aminophenazone breath-test according to the Haustein-Schenker modification was performed. The results were related to morphological, clinical and haemodynamic criteria. In contrast to a control group, consisting of 8 women and 8 men aged between 23 and 27 years with healthy livers, the aminophenazone elimination proved to be heavily delayed (p less than 0.001). In consideration of the Havanna-classification the 14CO2-elimination was most heavily retarded in patients with portal cirrhosis, but compared with non-portal cirrhosis, the difference was below significance level. A significant dependence on the clinical degree of severity was found. The aminophenazone-elimination was frequently low in portal hypertension and considerably decreased after portocaval shunt with values below 200 DPM/mmol CO2/70 kg body weight. In some cases it could be demonstrated, that the test is not only of diagnostic relevance, but reflects the progression of cirrhosis.

[Influence of exogenous factors on the behavior of aminophenazone breath test in chronic liver diseases]. / Untersuchungen zum Einfluss exogener Faktoren auf das Verhalten des Aminophenazon-Atemtestes bei chronischen Lebererkrankungen.

230 patients with different chronic liver diseases of various severity were researched because of the influence of nicotine and alcohol on the results of the aminopyrine breath test in the modification of Haustein and Schenker (1985). Smoker with chronic liver diseases had higher 14CO2-results than nonsmoker. The difference was only significant in fatty liver disease in the first stadium (p less than 0,001) and chronic active hepatitis (p less than 0.05). Patients with chronic liver diseases of fewer severity had higher mean values of aminopyrine breath test, if they had chronic alcohol consumption. The difference between these and abstinent patients could secure only in fatty liver disease in the first stadium (p less than 0.001). Patients with severe chronic liver diseases had lower results of aminopyrine breath test, if they drink alcohol regular. These difference was significant in patients with cirrhotic liver disease (p less than 0.05).

Interaction between nifedipine and cardioactive drugs.

Nifedipine (N) and dehydronifedipine (DHN) plasma levels were measured by gas chromatography in 37 patients before and 2 h after the intake of 20 mg N. They suffered from cardiovascular diseases and were treated with N in daily doses of 30 or 60 mg in combination with nitrates, beta-receptor blocking agents, digitoxin, saluretics and/or vasodilators for several weeks or months. Simultaneously, blood pressure and heart rate were measured. For comparison, six healthy volunteers between the ages of 25 and 46 years took 20 mg N on an empty stomach. Their mean plasma N level amounted to 47.7 (SD: 13.6) ng.ml-1, the DHN level reached a mean value of 46.7 (SD: 22.8) ng.ml-1 2 h after administration. The mean plasma N level of the patients rose from 14.1 to 34.1 ng.ml-1 and that of DHN, from 5.4 to 16.0 ng.ml-1. In 26 of 37 patients the heart rate increased without correlating with the altitude of the N level. The ratio DHN/N was 0.83 (SD 0.24) in the volunteers, while in the patients it amounted to 0.59 (SD 0.30). If the criterion DHN/N plasma level reached values greater than 1.0 the N degradation was enhanced (n = 4), and if it reached values less than 0.2, N degradation was depressed (n = 9). The results did not indicate inhibition of N degradation under long-term treatment with simultaneously administered cardioactive drugs.

[Behavior of the aminophenazone breath test in chronic liver diseases]. / Unterschungen zum Verhalten des Aminophenazon-Atemtestes bei chronischen Lebererkrankungen.

In 230 patients with histologically ascertained chronic hepathopathies the aminophenazone breathing test in the modification after Haustein and Schenker was carried out. In contrast to a control group consisting of 16 test persons with healthy liver (14CO2 exhalation 1019 +/- 175 DPM/mmol-CO2/70 kg body weight) the hepatic elimination of the [14C]-aminophenazone in chronic liver diseases (626 +/- 203 DPM/mmol CO2/70 kg body weight) was significantly restricted (p less than 0.001). The values of the aminophenazone breathing test showed a dependence on the degree of severity of the liver disease. Hepatoses with partly questionable or slight value of the disease did not differ in their results (841 +/- 230 DPM/mmol CO2/70 kg body weight) from those of persons with healthy liver. Chronic inflammatory liver diseases (668 +/- 185 DPM/mmol CO2/70 kg body weight) occupied an average position (p less than 0.001). The lowest values were to be seen in patients with chronic fibrosing liver diseases, mainly with liver cirrhosis (403 +/- 218 DPM/mmol CO2/70 kg body weight). Compared with the control group the difference was significant (p less than 0.001). Broad regions of overlapping of the individual values of various chronic liver diseases do not allow an unequivocal coordination of regions of the breathing test values to certain morphologically defined chronic hepatopathies. For the determination of size and degree of severity of the damage of liver parenchyma the aminophenazone breathing test, however, may be a valuable help in the framework of a special programme of diagnostics.

On the pharmacokinetics and metabolism of propiverine in man.

The pharmacokinetics of 14C-propiverine was studied in 13 volunteers and in 2 patients after a single i.v. injection of 5 mg or after oral administration of 15 mg. To each dose 1.11 MBq 14C-propiverine was added. The radioactivity measured in plasma, urine (and bile fluid), and the metabolites were estimated by an extraction procedure together with TLC and radiochromatography. Propiverine was eliminated from the plasma with a half-life time (t0.5) of 4.1 h (i.v. and per os), while the plasma radioactivity decreased with a t0.5 of 21.2 (i.v.) or 10.4 h (per os). Within 4 days, 84.5 (i.v.) or 53.5% (per os) of the administered radioactivity was excreted in urine. The absorption of radioactivity of propiverine amounted to 84.5%, while the amount of available propiverine was only 48.9%. In two patients with cannulated ductus choledochus, 21.5 or 14.7% of the administered radioactivity was excreted within 2 days. The metabolic pattern of plasma, urine and bile fluid mainly consisted of amine oxides, substances oxidized in the propyl side chain, desalkylated metabolites, substances with a N-demethylated piperidino group or with ester cleavage, and glucuronide conjugates. Unchanged propiverine appeared in plasma, urine and bile at about 6 to 8% of the administered dose.

Studies on the metabolic pattern of propiverine in urine after single administration.

In 11 healthy volunteers the metabolic pattern of propiverine [1; alpha, alpha-diphenyl-n-propoxy-1, 2-acetic acid-4-(1-methyl-piperidinyl)ester] was studied in urine after a single i.v. (5 mg) or oral dose (15 mg). To each dose 30.4 microCi (1.11 MBq) 14C-1 were added. The various urine fractions (0-1, 1-4, 4-8, 8-24 h) were extracted by chloroform and ethyl acetate at different pH-values and TLC was performed. The metabolites were identified by comparison of the RF-values of the radiochromatograms with those of the reference compounds after TLC using various solvent mixtures. Evidence for identity of the metabolites was additionally obtained by ester hydrolysis, ether cleavage or reduction with subsequent TLC after elution of the spots from the plate. The formed products were rechromatographed. 1 undergoes an extensive biotransformation: about 70% of the radioactive substances in urine consisted of 19 different metabolites, while 1 amounted to only 3%. Additionally, 3 acidic metabolites of unknown structure were isolated. Due to the metabolic pattern the following reactions of degradation were found: oxidation of the tertiary nitrogen in the piperidinyl moiety yielding N-oxides (40 to 50% of radioactivity), oxidation of one of the three carbon atoms of the propyl side chain, oxidation of the N-methyl group resulting in N-demethylated products, and ester cleavage. Propiverine N-oxide (20 to 25%) was determined as a major metabolite, whereas demethylated products occurred in minute amounts (1%). There was no evidence for oxidation of both phenyl moieties.

The 14C-aminophenazone breath test in pesticide workers.

In 59 workers between the ages of 22 and 66, who had been exposed to pesticides, and 31 healthy controls between the ages of 22 and 28, the hepatic demethylation capacity was studied using the aminophenazone breath test (ABT). The ABT was carried out in two versions (version A: 111 kBq 14C-aminophenazone per 630 mg, version B: 111 kBq 14C-aminophenazone per 3 mg). The amount of 14CO2 expired per mmol CO2 per 70 kg body weight (b.w.) detected 1 h after 14C-aminophenazone intake was used to determine the demethylation capacity of the liver. The amount of expired 14CO2 depended on the ingested dose (B greater than A). The 14CO2-values measured in 13 controls did not differ from those obtained in 37 subjects who had been exposed to pesticides for 650 h per year on the average [649 vs 726 DPM/mmol X 70 kg b.w. (A)]. The 14CO2-values obtained in 22 subjects exposed to pesticides for 990 h per year on the average (B) were lower than those obtained in 18 healthy controls (736 vs 1024 DPM/mmol CO2 X 70 kg; P less than 0.05). The 14CO2-values of ABT decreased with increasing length of exposure per year (B; r = -0.51, P less than 0.05).

[Bioavailability of etilefrine from Thomasin and Thomasin sustained-release tablets]. / Zur Bioverfügbarkeit von Etilefrin aus Thomasin- und Thomasin retard-Tabletten.

In 6 healthy volunteers absorption and elimination of etilefrine were studied in cross-over after intake of 20 mg each of a solution (A) and tablet (B) (Thomasin) or after intake of 25 mg as a sustained-release tablet (C; Thomasin retard). Etilefrine and its sulfoconjugate were measured by the GC technique in plasma and urine. From the data obtained the AUC-(plasma) and CUE-values (urine) were calculated. Peak plasma levels of 10 to 25 (A) and 6 to 13 ng . ml-1 were observed 30 min after intake. The concentrations decreased to the lower detection limit (less than 2 ng . ml-1) 2 h after intake. Plasma peak levels of 5 ng . ml-1 were measured 1-2 h after intake of the sustained-release form (C). The etilefrine plasma level decreased more slightly (C) than after intake of the other formulations (A, B). The etilefrine conjugate reached plasma peak concentrations of 600 ng . ml-1 1 h (A, B) or 2 h (C) after intake. A mean bioavailability of 70 and 58 per cent (Thomasin) or of 78 and 108 per cent (Thomasin retard) was calculated by comparison of the corresponding AUC- and CUE-values of the total etilefrine.

[Hepatic clearance of aminopyrine in the evaluation of liver function in hormonal contraception]. / Die hepatische Ausscheidung von Aminopyrin zur Beurteilung der Leberfunktion bei hormoneller Kontrazeption.

The function of microsomal destructing medicaments enzyme systems of the liver cell under hormonal contraception was objectified with the help of the aminopyrine test. After the oral administration of 9 mg dimethylaminoantipyrine (DMAAP) per kg body-weight together with 111 kBq 14C-DMAAP the elimination of 14CO2 was measured on the basis of the decrease of the radioactivity in the expiration air (respiration test). The plasma levels of DMAAP and its metabolites were measured, too. The two measurements lasted 5 hours. In contrast to a control group consisting of 8 women with healthy liver who were not ovulostatically treated (half-value time 14CO2-DMAAP 2.9 +/- 0.8 h, plasma 2.2 +/- 0.5 h) in 20 test women with healthy liver under ovulation inhibitors the elimination of 14CO2-DMAAP with 4.7 +/- 1.6 was clearly (alpha less than 0.01), the plasma elimination with 3.0 +/- 0.8 h was slightly retarded (alpha less than 0.05). In 19 patients with histologically ascertained chronic hepatopathies of above all insignificant degree of severity (13 degenerative lesions of liver parenchyma, 3 fatty livers stage I or II, 1 chronic active hepatitis each, chronic persisting hepatitis and cirrhosis) under hormonal contraception a half-value time of the 14CO2 elimination (alpha less than 0.001) prolonged to 5.0 +/- 1.5 h and a prolongation of the plasma elimination to 3.8 +/- (alpha less than 0.05). In 9 women in double examinations the 14CO2 elimination of the DMAAP after discontinuation of the application of ovulation inhibitors was compared with the values obtained under hormonal contraception and a regression of the retarded excretion in the expiration air (4.2 +/- 2.3 less than 5.1 +/- 1.2 h) and plasma (2.6 +/- 0.7 less than 3.4 +/- 1.7) was proved.(ABSTRACT TRUNCATED AT 250 WORDS)

The determination of aminopyrin elimination for control of the metabolic capacity of the liver in man.

The kinetics of plasma and breath elimination of aminopyrine after 14C-aminopyrine given orally were studied using an open one-compartment model and first order rates of elimination. The study comprised eight healthy volunteers and two groups with histologically verified chronic liver diseases (cirrhosis, n = 12, and chronic aggressive hepatitis, n = 12). Elimination rates from plasma and breath were significantly reduced in the group with cirrhosis, but only so in chronic aggressive hepatitis when they were expressed relative to each other. Monomethylaminopyrine was eliminated more rapidly compared to aminopyrine, and the rate of formaldehyde formation was positively correlated to the excretion rate of CO2 (r = 0.53, P less than 0.002). No correlation was found with clinical or other laboratory data in the groups of liver diseases studied. The test is a quantitative indicator of the drug metabolizing mixed function oxidases of the endoplasmatic reticulum of the liver, and may reflect the degree of damage to this system in chronic liver disease.

[Quantitative thin-layer chromatographic estimation of aminophenazone (I.N.N.), 4-methylaminophenazone and 4-aminophenazone in plasma (author's transl)]. / Quantitative dünnschichtchromatografische Bestimmung von Aminophenazon (I.N.N.), 4-Methylaminophenazon und 4-Aminophenazon im Plasma.

A TLC method for measurement of aminophenazone (1) and of its degradation products 4-methylaminophenazone (2) and 4-aminophenazone (3) in plasma was described. After chloroform extraction amd separation on Silufol plates the substances were stained by ferric chloride/potassium hexacyanotoferrate(III) and the area of the spots was measured. Concentrations from 1 to 25 micrograms 1, 2 and 3 per ml plasma could be estimated.

On the plasma protein binding of 16-acetyl-gitoxin.

The plasma protein binding of 16-acetyl-gitoxin (16-AG) was estimated in comparison with that of digoxin by the use of equilibrium dialysis, ultracentrifugation, and gel filtration techniques. Depending on temperature, the binding of 16-AG reached values between 81 and 90%. Calculations of the reaction enthalpy and entropy show that hydrophobic interaction results. The corresponding values of digoxin amount to 13 and 15%.