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Tramadol is a centrally acting analgesic drug that has been used clinically for the last two decades to treat moderate to moderately severe pain in humans. The present study investigated tramadol administration in horses by intravenous, intramuscular, oral as immediate-release and oral as sustained-release dosage-form routes. Seven horses were used in a four-way crossover study design in which racemic tramadol was administered at 2 mg/kg by each route of administration. Altogether, 23 blood samples were collected between 0 and 2880 min. The concentration of tramadol and its M1 metabolite were determined in the obtained plasma samples by use of an LC/MS/MS method and were used for pharmacokinetic calculations. Tramadol clearance, apparent volume of distribution at steady-state, mean residence time ( MRT) and half-life after intravenous administration were 26 ± 3 mL/min/kg, 2.17 ± 0.52 L/kg, 83 ± 10 min, and 82 ± 10 min, respectively. The MRT and half-life after intramuscular administration were 155 ± 23 and 92 ± 14 min. The mean absorption time was 72 ± 22 min and the bioavailability 111 ± 39%. Tramadol was poorly absorbed after oral administration and only 3% of the administered dose was found in systemic circulation. The fate of the tramadol M1 metabolite was also investigated. M1 appeared to be a minor metabolite in horses, which could hardly be detected in plasma samples. The poor bioavailability after oral administration and the short half-life of tramadol may restrict its usefulness in clinical applications. [ABSTRACT FROM AUTHOR]

BACKGROUND: This study evaluated the optimal formulation (tablet vs solution) and frequency (once vs twice daily) of maintenance oral furosemide in compensated congestive heart failure (CHF). METHODS AND RESULTS: Eighteen patients with mild (group 1) and 18 with severe (group 2) CHF were studied. On 2 consecutive days each patient's individual fixed oral furosemide daily dosage was administered in tablet or solution in a crossover design. In an additional study, 14 patients with severe CHF received the daily dosage in tablet or solution form in two divided doses. Pharmacokinetic data were obtained in six randomly allocated patients of each group, during the once daily administration periods of either formulation. Twenty-four-hour urinary sodium and 12-hour volume were significantly greater in group 1 following furosemide solution versus tablets. In group 2, all parameters were comparable in response to single identical doses in tablets or solution, as well as to once versus twice daily administration of either formulation. These results coincided with a higher C(max) and a shorter t(max) following solution. CONCLUSIONS: A once-daily oral furosemide solution is more effective than the same dosage in tablet form in patients with mild, but not those with severe, CHF. In patients with severe CHF, the natriuretic and diuretic effects are similar whether oral furosemide in tablet or solution is administered in a once or twice daily schedule. [ABSTRACT FROM AUTHOR]

The minimal inhibitory concentrations (MIC) of cefazolin were determined for several species of pathogenic bacteria associated with infection in young calves. The MIC of the drug for 90% of the Escherichia coli, Salmonella spp., Pasteurella haemolytica and Aerobacter spp. was 3.12 μg/ml. The MIC 90 value of the drug for P. multocida and Citrobacter spp. was 1.56 μg/ml and for Klebsiella spp. and enterococci it was 6.25 μg/ml. Cefazolin was administered intravenously or intramuscularly alone and together with probenecid to groups of young calves. From analysis of serum drug concentration data, several distribution and elimination kinetic parameters were determined. The drug was distributed very rapidly in the body with a distribution half-life (t 1/2 α) of 7 minutes, the apparent specific volume of distribution at steady-state (Vd, ss') was 0.165 l/kg, the elimination half-life (t 1/2 β) after intravenous injection was 37 minutes but the t 1/2 i. m. was 55 minutes. Cefazolin was bound to serum proteins at 75% and the i. m. bioavailability (F) was 85%. The co-administration of cefazolin and probenecid i. m. resulted in the elevation and prolongation of serum cefazolin concentrations. Computations showed that in order to maintain potentially effective tissue concentrations against most pathogens cefazolin should be given every 8 hours at 13.5 mg/kg or every 12 hours at 20.2 mg/kg; these doses could be reduced by one-half with the co-administration of probenecid. Zusammenfassung Klinische Pharmakologie von Cefazolin bei Kälbern: Die minimale Hemmkonzentration (MIC) von Cefazolin wurde für verschiedene Species pathogener Bakterien bestimmt, die bei Infektionen von Kälbern vorkommen. Die MIC der Substanz für 90% von Escherichia coli, Salmonella spp., Pasteurella haemolytica and Aerohacter spp. lag bei 3,12 μg/ml. Der MIC 90-Wert der Substanz für P. multocida und Citrobacter spp. betrug 1,56 μg/ml, für Klebsiella spp. und Enterokokken lag er bei 6,25 μg/ml. Cefazolin allein und zusammen mit Probenecid wurde sowohl intravenös als auch intramuskulär (i. m.) bei jungen Kälbern appliziert. Aufgrund der Analyse der Serumkonzentrationen der Substanz wurden mehrere kinetische Verteilungs- und Eliminationsparameter bestimmt. Die Substanz verteilte sich im Körper sehr rasch (Verteilungshalbwertszeit, t 1/2 α = 7 min.). Das apparente spezifische Verteilungsvolumen im steady state (Vd, ss') betrug 0,165 l/kg. Die Eliminationshalbwertszeit (t 1/2 β) nach intravenöser Injektion betrug 37 min., t 1/2 i. m. lag bei 55 min. Cefazolin wurde zu 75% an die Serumproteine gebunden; die Bioverfügbarkeit (F) nach i. m. Injektion lag bei 85%. Die gemeinsame i. m. Applikation von Cefazolin und Probenecid bewirkte gegenüber der alleinigen Applikation von Cefazolin erhöhte Serum-Cefazolin-Konzentrationen. Ferner blieb die Cefazolin-Konzentration länger erhöht. Nach entsprechenden Berechnungen sollte zur Aufrechterhaltung einer potentiell wirksamen Gewebskonzentration von Cefazolin gegen die meisten pathogenen Keime Cefazolin alle 8 h in einer Dosierung von 13,5 mg/kg oder alle 12 h in einer Dosierung von 20,2 mg/kg verabreicht werden. Diese Dosierungen könnten durch die gleichzeitige Applikation von Probenecid um die Hälfte reduziert werden. [ABSTRACT FROM AUTHOR]

Erythromycin base was injected intravenously to 2-3-week-old calves and 10-12-week-old calves and the distribution and elimination kinetics of the drug were determined from analyses of serum drug level data. The disposition kinetics of the drug in calves of the two age groups were very similar and were characterized by a distribution half-life (t 1/2α) of 18 minutes, an elimination t 1/2β of approximately 2.5 hours, an apparent specific volume of distribution (V'd) 1.4 times larger than total body volume, and a wide (1.6) overall tissue-to-serum concentration ratio during the time of apparent distribution equilibrium (K12/K21). After erythromycin base was administered orally as a drench at 10 mg/kg to 2-3-week-old calves the antibiotic was not detected in the serum. Erythromycin thiocyanate was given orally to pre-ruminant (2-3-week-old) calves at 10 mg/kg and 20 mg/kg, and to early ruminant (7-8-week-old and 10-12-week old) calves at 20 mg/kg and 40 mg/kg, respectively. The 10 mg/kg and the 20 mg/kg oral doses of erythromycin thicyanate in pre-ruminant calves resulted 4 hours later in mean peak serum concentrations of 0.46 μg/ml and 2.21 μg/ml, respectively, and the oral bioavailability was 8.6% and 24.5%, respectively, of the doses given. In contrast, the 20 mg/kg dose and the 40 mg/kg dose given orally to early ruminant calves produced low, variable and erratic serum drug levels. Oral erythromycin thiocyanate therapy should, therefore, be restricted to pre-ruminant calves. In view of the large Vd of the drug and its reported wide distribution throughout the body and accumulation in many organs, notably the lung, at concentrations well above serum levels, oral erythromycin thiocyanate therapy at 20 mg/kg every 12 hours seems justified for the treatment of infections in newborn calves due to erythromycin-sensitive microorganisms. Zusammenfassung Altersabhängigkeit der Bioverfügbarkeit von oral verabreichtem Erythromycinthiozyanat bei Kälbern: Erythromycinbase wurde bei 2-3 und 10-12 Wochen alten Kälbern intravenös injiziert. Anschließend wurde die Verteilungs- und Eliminationskinetik der Substanz anhand des Verlaufs des Serumspiegels bestimmt. Die Verteilungskinetik der Substanz war bei den Kälbern beider Altersgruppen sehr ähnlich. Sie wies folgende Charakteristika auf: Verteilungshalbwertszeit (t 1/2 α): 18 min, Eliminationshalbwertszeit (t 1/2β): ungefähr 2,5 h, scheinbares spezifisches Verteilungsvolumen (V'd): 1,4-mal größer als das gesamte Körpervolumen, weites Gesamtgewebe- zu Serumkonzentrations-Verhältnis (1,6) während des scheinbaren Verteilungsgleichgewichts (K12/K21). Nach oraler Verabreichung der Erythromycinbase als Latwerge in einer Dosierung von 10 mg/kg bei 2-3 Wochen alten Kälbern konnte das Antibioticum im Serum nicht nachgewiesen werden. Erythromycinthiozyanat wurde oral an Milchkälber (2-3 Wochen alt) in einer Dosierung von 10 mg/kg und 20 mg/kg, an ruminierende Kälber (7-8 Wochen und 10-12 Wochen alt) in einer Dosierung von 20 mg/kg und 40 mg/kg verabreicht. Die Dosierungen von 10 mg/kg und 20 mg/kg führten bei Milchkälbern nach oraler Verabreichung von Erythromycinthiozyanat 4 h später zu maximalen Serumkonzentrationen von im Mittel 0,46 μg/ml bzw. 2,21 μg/ml. Die Bioverfügbarkeit betrug 8,6% bzw. 24,5% der oral verabreichten Dosis. Demgegenüber hatten die Dosierungen von 20 mg/kg und 40 mg/kg nach oraler Verabreichung an ruminierende Kälber niedrige und sehr variable Serumkonzentrationen der betreffenden Substanz zur Folge. Die orale Erythromycinthiozyanat-Therapie sollte daher auf Milchkälber beschränkt werden. In Anbetracht des großen Vd des betreffenden Arzneimittels, seiner weiten Verteilung über den ganzen Körper und seiner Akkumulation in vielen Organen, vor allem aber in der Lunge, in Konzentrationen weit über dem Serumspiegel scheint die orale Erythromycinthiozyanat-Therapie in einer Dosierung von 20 mg/kg alle 12 h für die Behandlung von Infektionen neugeborener Kälber mit Erythromycin-sensitiven Microorganismen gerechtfertigt. [ABSTRACT FROM AUTHOR]

The article discusses the use of dependent-absorption apparent volume distribution at steady state (Vss/F) on pharmacokinetic analysis. It mentions that pharmacokinetic analysis is limited particularly those that are based on administration data from extravascular drug. It also states that the use of (Vss/F) in pharmacokinetic analysis determined by compartmental analysis is harmful and is strongly discouraged.