Pharmacokinetics of acetazolamide in healthy volunteers after short- and long-term exposure to high altitude.

Exposure to high altitude results in significant physiologic changes and may precipitate mountain sickness, ranging from mild symptoms above 2,500 m to severe symptoms above 4,000 m. In a previous study, changes in the pharmacokinetics of meperidine were observed after exposure to high altitude. This study was conducted to investigate whether similar changes occur for acetazolamide, which is prescribed for prophylaxis of acute mountain sickness. Acetazolamide 250 mg was administered orally to young, healthy male volunteers in groups of 12 each: those residing at sea level (group L), these same volunteers on the day after arrival at high altitude (4,360 m, group HA), and volunteers living at high altitude for 10 months or longer (group HC). Serial blood samples were collected for 24 hours and acetazolamide concentrations were measured in whole blood, plasma, and plasma water. The elimination rate constant (lambda z) was significantly increased in group HA compared with group L. Clearance uncorrected for bioavailability (Cl/F) increased significantly in group HA compared with group L, and further increased in group HC. Apparent volume of distribution (Vz/F) was decreased by 17% in group HA compared with group L, and increased by 37% in group HC compared with group HA. Mean residence time (MRT) was significantly decreased in group HA compared with groups L and HC. Erythrocyte (RBC) uptake increased significantly after a significant increase in RBC count in group HC compared with group L. The extent of protein binding (EPB), however, was significantly decreased in group HA compared with groups L and HC. Free acetazolamide concentrations were significantly lower in group HC than in group L 12 hours after administration. Based on these observations, it is suggested that patients travelling to high altitude, especially altitudes above 4,000 m, should be closely monitored and acetazolamide dosage adjusted as necessary.

Urinary excretion of acetazolamide in healthy volunteers after short- and long-term exposure to high altitude.

Acetazolamide is recommended for the prophylaxis of acute mountain sickness symptoms which sets in on climbing to high altitudes (H) above 2,500 m. It is primarily excreted unchanged in urine. In a previous study, we reported on the changes in urinary excretion of meperidine and its metabolite normeperidine on exposure to high altitude. In this study, we investigated the effect on urinary excretion of acetazolamide. The study was carried out in three groups of 12 healthy male volunteers each: at sea level (group L), these same volunteers the day after arrival at high altitude of 4,360 m (group HA), and subjects residing for approximately 10 months at high altitude (group HC). Urine was collected for the periods of 0-2, 2-4, 4-8, 8-12, 12-24 and 24-36 h after peroral administration of a single 250 mg dose. Urinary pH was measured and the concentrations of acetazolamide were determined. There were no significant changes observed in the amount of acetazolamide excreted in urine over 36 h. The urinary pH ranged from 4.5 to 7.8 for L, from 4.2 to 6.9 for HA and from 3.1 to 6.7 for HC. The Fel (fraction eliminated unchanged in urine) was calculated from the amount excreted in 36 h in urine and dose, assuming a bioavailability of 1 based on literature data. No significant changes in Fel were seen.

Pharmacokinetics of meperidine in healthy volunteers after short- and long-term exposure to high altitude.

Increased numbers of erythrocytes have been shown ex vivo to increase meperidine uptake, and one of the major physiologic changes that occurs at high altitude is an increase in hematocrit and erythrocytes. A study was therefore conducted to evaluate the effects of high altitude on the pharmacokinetics of meperidine. Intramuscular doses (0.75 mg/kg) of meperidine were given to three groups of healthy volunteers (age range, 18-20 years): participants living at sea level (group L), those same participants the day after arrival at high altitude (4,360 m; group HA), and participants who had lived at high altitude for > or = 10 months (group HC). Blood samples were collected for 12 hours after drug administration. Meperidine was measured in whole blood, plasma, and plasma water. Elimination rate constant (lambda z) and clearance uncorrected for bioavailability (Cl/F) were significantly lower at high altitudes than at sea level in plasma (HA and HC) and in whole blood (HA only). Mean residence time (MRT) was significantly higher at high altitudes than at sea level in plasma (HA and HC) and in whole blood (HA only). Hematocrit was significantly increased at both time points at high altitude in comparison to values at sea level, and was also higher after a long-term stay at high altitude than after arrival at high altitude. Erythrocyte binding increased significantly from 41.3% at sea level to 43.8% at arrival at high altitude to 50.9% after a long-term stay at high altitude. The extent of protein binding tended to decrease with high altitude, but this decrease was not significant. Free concentrations of meperidine in plasma water measured 1, 2, and 4 hours after administration were significantly increased after 2 and 4 hours.

Urinary excretion of meperidine and normeperidine in man upon acute and chronic exposure to high altitude.

The urinary excretion of unchanged meperidine (M) varies with change of pH and metabolism. Since exposure of man to high altitude (H) may cause significant physiologic changes, we investigated its effects on the urinary excretion of M. The study was carried out in 3 groups of healthy, male volunteers (ages 18-20 years): at sea level (L), at 4360 m the day after arrival at H (HA), and at 4360 m in subjects residing for > 10 months at H (HC). Urine was collected for the periods of 0-4, 4-8, 8-12 and 12-24 h. Urinary pH was measured and the concentrations of M and normeperidine (N) were determined. The 24 h excretion of M and N was significantly decreased for L vs. HA and L vs. HC. Significance was also seen for the periods 0-4, 4-8 and 8-12 h. The ratio of amount excreted M/N for the 24 h period was highly significant for L vs. HA and L vs. HC. The urinary pH ranged from 5.3-5.9 for L, 5.9-7.0 for HA, and 5.1-5.7 for HC. The Fel (fraction of M eliminated in the unchanged form in urine) significantly decreased from L to HA and HC.

Meperidine uptake and binding to human blood ex vivo.

Many drugs are bound to plasma proteins (PR) and/or to erythrocytes (RBC). The RBC count may change due to physiologic factors such as exposure to high altitude, or pathologic conditions such as anemia or as consequence of cancer treatment. The purpose of the investigation was to study the influence of 1) drug concentration, and 2) number of RBC on erythrocyte uptake or binding using meperidine as a model drug (M). Human RBC concentrated blood was used and blood chemistry determined. Using human plasma (P) dilutions were made containing 9.9, 7.62, 5.87 and 4.11 million RBC mm3. The whole blood (WB) samples were spiked with M to result in 10, 25, 50, or 75 micrograms/ml. Increasing concentrations of M within each group of same RBC count did not influence percentage of erythrocyte uptake/binding. Increase in RBC count from 4.11 to 9.9 million/mm3 resulted in significant increase in erythrocyte uptake from 77.1% to 94.7% and increase in PR binding from 37.2% to 87.4%.

[Study on possible interactions between tiaprofenic acid and phenprocoumon (author's transl)]. / Untersuchung zur Frage einer Interaktion von Tiaprofensüre and Phenprocoumon.

The study deals with the clinical and pharmacokinetic interaction of tiaprofenic acid (Surgam) and phenprocoumon. 6 healthy volunteers received phenprocoumon p.o. with a view to decreasing Quick's value. After the first administration a pharmacokinetic profile of phenprocoumon was taken. As Quick's value dropped to 37% at the 4th day of the study, the subjects received tiaprofenic acid additionally. Afterwards the pharmacokinetic profiles of phenprocoumon and tiaprofenic acid were taken again. The study led to the following results: 1. The clotting parameters are not changed on synchronous administration of tiaprofenic acid and phenprocoumon. 2. The pharmacokinetic profile of tiaprofenic acid is not changed by pretreatment with phenprocoumon. 3. The parmacokinetic profile of phenprocoumon is not changed by tiaprofenic acid.

[Human pharmacokinetics of theophylline and etofylline from different formulations of a cardiotonic (author's transl)]. / Zur Humanpharmakokinetik von Theophyllin und Etofyllin aus verschiedenen Zubereitungen eines Kardiotonikums.

Serum concentrations of theophylline and etofylline were analysed by a specific HPLC-method in 6 volunteers after i.v. and p.o. administration of the cardiotonic Cordalin ampoules, drops and dragees. Maximum serum concentrations were reached by theophylline an etofylline at about the same time: 1.0-1.2 h after Cordalin drops; 2.3-2.6 h after Cordalin dragees. The half-life of serum elimination was 5.0-7.2 h for theophylline and 5.5-6.9 h for etofylline. The absolute bioavailability of the two oral formulations was calculated from the areas under the serum curves. For theophylline it is complete from the dragees and 78% from drops. Etofylline, too, is highly bioavailable: 94% from the dragees, 84% from drops. From the kinetic data the conclusion can be drawn that accumulation of theophylline and etofylline will be negligible after Cordalin if administered according to prescribed directions.

[On the pharmacokinetics of tiaprofenic acid and its possible interactions with acetylsalicylic acid and aluminum hydroxide (author's transl)]. / Zur Pharmakokinetik von Tiaprofensäure und zur Frage der Interaktion mit ASS und Aluminiumhydroxid.

To clarify the question whether pharmacokinetic properties of tiaprofenic acid (presumable trade name Surgam) can be changed by simultaneous application of aluminum hydroxide or acetylsalicylic acid (ASA) a randomized study of 7 healthy volunteers was carried out. The results show that the bioavailability as well as the pharmacokinetic profile of orally administered tiaprofenic acid is not changed by the mentioned compounds.

Biopharmaceutic evaluation of etofylline clofibrate and its drug formulation.

The biopharmaceutic criteria of Duolip and its active principle, 1-(theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methylpropionate] (etofylline clofibrate, ML 1024), are described. ML 1024 was found to be practically insoluble in water at pH values ranging from 2 to 7.4 and in human serum. A very low dissolution rate of the drug from the capsule preparation was found in artificial gastric and intestinal fluid, along with little cleavage to the individual components clofibric acid and etofylline. The particle size was mainly less than 40 micrometers. For the classification of granules the granule size, the angle of repose (tan alpha), the flow time, the stamp volume and the packing factor were determined.

[Metabolism and pharmacokinetics of etofylline clofibrate, new antilipemic]. / Metabolismus und Pharmakokinetik von Etofyllinclofibrat, einem neuen Antilipmikum.

Upon investigations on metabolism and pharmacokinetics of 1-(theophyllin-7-yl)-ethyl-2-[2-(chlorophenoxy)-2-methylpropionate] (etofylline clofibrate, ML 1024, Duolip) is reported. As can be seen from in vivo tests in rats and dogs ML 1024 is cleaved to the metabolites clofibric acid and etofylline. This could be further demonstrated in vitro by incubation with lipases and human serum. The pharmacokinetic parameters of the metabolites after oral application of 2 capsules Duolip, corresponding to 500 mg etofylline clofibrate, were evaluated in 7 healthy volunteers. The serum fluctuations of the main metabolites could be adapted to an open two-compartment model (etofylline). The following mean values were found: the invasion half-life is 1 h 4 min for clofibric acid and 1 h 52 min for etofylline. The maximum concentration after approximately 4 h is 22.75 micrograms/ml for clofibric acid and 6.57 micrograms/ml for etofylline. The elimination half-life is 12.12 h for clofibric and 4.33 h for etofylline. Via urine 20 mg clofibric acid and 15.7 mg etofylline were excreted within 8 h. The elimination process after 8 h is not yet terminated.

[Pharmacokinetic analysis of a benzarone preparation. First communication: analytical method (author's transl)]. / Pharmakokinetische Analyse einer Benzaron-Zubereitung. 1. Mitteilung: Analysenmethode.

A new analytical method to determine 3-(4-hydroxybenzoyl)-2-ethyl-benzofurane (benzarone, Fragivix) from human serum and urine is described. The substance is extracted from the biological fluids with chloroform after cleavage of the glucuronide with glucuronidase. Benzarone is detected with the HPLC with a special design method on the base of a gradient elution on a reversed-phase column. The method is suitable to measure the necessary concentrations for a kinetic analysis in the serum as well as in the urine. The limit of assessment could be detected at 0.03 microgram/ml. The serum concentration-time curve after oral as well as after i.v. application could be detected with the method.

[Relative bioavailability of a new spironolactone preparation (author's transl)]. / Relative Bioverfügbarkeit einer neuen Spironolacton-Zubereitung.

The investigations have been performed to determine the relative bioavailability of canrenon from Acelat 100 capsules in comparison with canrenon from a spironolactone standard preparation available on the German market. This was carried out by comparing the areas under the serum fluctuation curves after oral application of both preparations as well as by urine excretion extrapolated infinitely. The preparations were administered together with a standard breakfast. Subsequently up to 48 h blood was withdrawn from the Vena cubiti. According to a known method serum samples were analysed spectrophotometrically. The data obtained were fitted to an open two-compartment model with the RIP-procedure. The core of the program is a Gauss-Newton iteration (minimising the last squares). These are the results: By intraindividual comparison of the areas under the serum fluctuation curves of canrenon a relative bioavailability of 116.27% (s = 16.84) of canrenon from Acelat 100 could be calculated versus canrenon from the standard. Urine excretion, extrapolated infinitely, showed a 4% higher excretion of canrenon after application of Acelat 100 compared to standard. Both results are not significantly different in the range of biological scattering. The further pharmacokinetic parameters calculated were within the range of the literature available.

[Circadian fluctuations of pharmacokinetic parameters after oral administration of hexobarbital (author's transl)]. / Zirkadiane Schwankungen pharmakokinetischer Parameter nach oraler Gabe von Hexobarbital.

To 4 male and 2 female subjects hexobarbital was applied orally at different times of the day: 2, 10, 18 h. Serum concentrations of hexobarbital were determined by HPLC procedure and the resulting pharmacokinetic parameters in a rotating iterative program. Application at 18 h resulted in a shorter invasion time, a higher maximum concentration and a delayed elimination; in addition, the AUC was elevated in relation to application at 2 or 10 h. In the 2 female subjects a different pattern was observed. The results lead to the assumption that application of hexobarbital is more effective in the evening than in the morning.

[Relative bioavailability of a vincamine retard formulation. Pharmacokinetic study in normal subjects (author's transl)]. / Relative Bioverfürgbarkeit einer Vincamin-Retard-Zubereitung. Pharmakokinetische Untersuchungen an gesunden Versuchspersonen.

The study was carried out in 6 healthy volunteers in cross-over design. The pharmacokinetic parameters were calculated after application of 60 mg vincamine base in comparison to a sustained release formulation (vincamine ratio-pharm 30 mg) on the basis of a GC method. Summarizing it can be stated that the sustained release formulation has a flatter profile and is therefore more adapted to clinical application. The extent of absorption expressed as AUC of the serum concentration-time curve, has three times the extent of the curve with the pure substance.