Efecto del hidróxido de aluminio y magnesio en la farmacocinética de irbesartán / Effect of aluminum magnesium hydroxide in pharmacokinetics of irbesartan

Objetivo. Determinar si la farmacocinética de irbesartán en dosis única se altera significativamente tras la administración de hidróxido de aluminio y magnesio (Unimaalox®). Métodos. Estudio abierto, randomizado, de 3 vías de tratamiento, en el que se incluyeron 18 voluntarios sanos. Los días 1, 8 y 15 de tratamiento los voluntarios recibieron por vía oral y en ayunas uno de los siguientes tratamientos: irbesartán 300 mg, irbesartán 300 mg + 10 ml de Unimaalox® suspensión concomitantemente, o irbesartán 300 mg + 10 ml de Unimaalox® suspensión 2 horas antes de la administración de irbesartán. Las muestras sanguíneas se recogieron en los tiempos especificados en el protocolo y hasta 48 horas, tomando como tiempo 0 la administración de irbesartán. Las concentraciones plasmáticas de irbesartán se determinaron mediante HPLC utilizando una técnica validada con extracción en fase sólida. Resultados. No se hallaron diferencias estadísticamente significativas en cuanto a la concentración plasmática máxima (Cmáx) o área bajo la curva de las concentraciones plasmáticas hasta las 48 horas (AUC0-48) postadministración entre los distintos tratamientos administrados. En el caso del AUC extrapolada al infinito (AUC0- ), las diferencias halladas entre los distintos grupos de tratamientos fueron estadísticamente significativas (p = 0,038) cuando se comparó la administración de irbesartán sólo frente a irbesartán más Unimaalox® administrado en las 2 horas previas (p = 0,021). Sin embargo, el intervalo de confianza al 90 por ciento para AUC0- se situó entre 0,67 y 1,5. La mediana para el tiempo en alcanzar la Cmax (tmax) fue de 2,5 horas en todos los grupos de tratamiento. Conclusiones. Estos resultados sugieren que no hay interacción entre el hidróxido de aluminio y magnesio e irbesartán. Por tanto, no es necesario realizar un ajuste de la dosificación cuando se administran concomitantemente (AU)

Irbesartan does not affect the steady-state pharmacodynamics and pharmacokinetics of warfarin.

OBJECTIVES: To determine whether the initiation or titration of irbesartan alters the pharmacodynamics and/or pharmacokinetics of warfarin in a clinically significant manner, thereby requiring additional monitoring of the anticoagulant effect of warfarin. METHODS: Daily doses of warfarin were administered to 16 healthy males for 21 days (10 mg on day 1 and 2.5-10 mg on days 2-21). Irbesartan (300 mg/day) or placebo was concomitantly administered on days 15-21. The pharmacodynamic parameters prothrombin time (PT) and prothrombin time ratio (PTR) were evaluated throughout the study. Plasma and urine samples were collected before and up to 24 h after administration on days 14, 15 and 21 for the determination of the maximum concentration (C(max)), time to reach C(max)(t(max)), the area under the concentration-time curve (AUC) of S-warfarin and the cumulative urinary excretion of warfarin and its metabolites. Pre-dose plasma samples were also collected to determine the C(min) of S-warfarin (days 12, 13, 14 and 21) and irbesartan (days 19, 20 and 21). RESULTS: Analysis of PTR data revealed no significant difference between the group mean PTR values at day 22 and those at day 15 (P=0.699). S-warfarin concentrations in plasma and urine, as well as the urinary concentrations of the metabolites of warfarin, were not affected by concomitant single- or multiple-dose administration of irbesartan. Plasma C(min) concentrations of S-warfarin and irbesartan were also not affected. CONCLUSIONS: No clinically important effect of irbesartan on the pharmacodynamics and pharmacokinetics of warfarin are likely to occur during concomitant administration; therefore, neither a dosage adjustment of irbesartan or warfarin nor any additional monitoring of the anticoagulant effect of warfarin is necessary.

Influence of food intake on the bioavailability of urapidil in healthy volunteers.

The influence of food intake on the pharmacokinetics of a single dose (30 mg) of urapidil in a tablet and a sustained-release capsule form were examined in 12 healthy volunteers in a double crossover trial. Drug administration under fasting conditions requires that a standardized breakfast be eaten, 4 h after drug intake. Drug application with breakfast requires drug intake with the standardized breakfast. Blood was sampled and blood pressure measured before and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 21, 28 and 32 h after drug administration. Urapidil was determined by HPLC. AUC, Cmax, tmax and t1/2 were calculated. Food intake did not influence the bioavailability of urapidil in tablet form. After the administration of the sustained-release capsule Cmax and tmax were increased while t1/2 was decreased by food intake. Despite these differences, the AUC was not influenced by concomitant food intake with the sustained-release capsule. In the fasting state, the AUC of the sustained-release capsule was 28% lower than that of the tablet. Food intake together with the sustained-release capsule abolished this difference. Since blood pressure decreases in hypertensive patients treated with urapidil are most pronounced in the inclining part of the urapidil-serum concentration curve, maximizing this part of the curve, as is the case with the administration of the sustained-release capsule together with breakfast, should be advantageous. Therefore, the suggestion that the sustained-release capsule be taken with breakfast is of therapeutic significance.

[The pharmacokinetics and bioavailability of urapidil. In vitro/in vivo correlations of different experimental formulations]. / Zur Pharmakokinetik und Bioverfügbarkeit von Urapidil. In-vitro-/in-vivo-Korrelation verschiedener experimenteller Zubereitungen.

The pharmacokinetic parameters, including the relative bioavailabilities of two experimental batches of a 60-mg urapidil slow release-capsule and a 30-mg urapidil drinking ampoule (Ebrantil) had to be evaluated in a randomized, three-period change-over study with 12 healthy volunteers after single dosing. The appropriate parameters for the capsule formulations were compared with their dissolution rates obtained by different in vitro models. The capsules showed different half-change, but comparable single-fluid dissolution profiles. Both batches of the capsules showed equivalence with respect to the extent of absorption, in connection with 100% relative bioavailability on average. A correlation of the in vivo parameters Tmax and Cmax with the half-change model can be assumed.

Pharmacokinetic profile of metaclazepam (Talis), a new 1.4-benzodiazepine. Influence of different dosage regimens on the pharmacokinetic profile of metaclazepam and its main metabolite under steady-state conditions.

The pharmacokinetic parameters of the new 1.4-benzodiazepine metaclazepam (Talis) were investigated. In particular, the question of whether the drug and/or its main metabolite accumulates in the body under steady-state conditions was studied. Two dosage regimens were compared by a randomized two-way crossover design: a once-a-day dosing (15 mg metaclazepam in the evening, = A) versus a twice-a-day dosing (5 mg in the morning plus 10 mg in the evening, = B) over ten days in twelve healthy male volunteers. Plasma levels of metaclazepam and its major biotransformation product, N-desmethylmetaclazepam, were determined. Comparing the treatments, significant differences were found for Cmax, but not for AUC-3 and Tmax. These results are also valid for the comparison of days 1 and 10 of each treatment. Higher Cmax values for dosage regimen A were found but Tmax and Cl/F remained stable in both treatments taking into account that 12 hours after the first medication, another dosing took place in treatment B. Eight hours after application, plasma levels were markedly low, Cmax values after single-dosing were nearly twice as high as after multiple dosing. Therefore based on these pharmacokinetic findings, a second dosing seems to be necessary; the clinical relevance needs further investigation. It has been reported, in fact, that it is in general very difficult to demonstrate a correlation between blood levels and therapeutic effects for 1.4-benzodiazepines (1,2).

[Pharmacokinetics and bioavailability of diphenhydramine in man]. / Pharmakokinetik und Bioverfügbarkeit von Diphenhydramin beim Menschen.

By the presented study the relative bioavailabilities and some important pharmacokinetic parameters should be evaluated after oral application of a single-dose of three different diphenhydramine (DPH, 2-diphenylmethoxy-N,N-dimethylethylamine)preparations in a randomized, cross-over design to 12 healthy volunteers. Additionally, some simple pharmacodynamic measurements of the volunteer's vigilance were performed and the question whether a combination with 8-chlorotheophylline influences the pharmacokinetic and/or pharmacodynamic profile of DPH was investigated. As the test preparations (Benocten as a tablet = A, as a buffered solution = B) contained 50 mg of DPH-HCl, but the reference preparation (= C) only 31 mg of DPH-HCl (+ 23 mg 8-chlorotheophylline), the biometric-statistic calculations had to be done with and without dose correction. Bioequivalence of the preparations could only then be demonstrated when the calculations were done with dose corrections: without these corrections for the reference preparation significantly lower serum levels resulted which hardly can be considered sufficient for exerting a sleep-inducing effect. The addition of 8-chlorotheophylline recommended by some other authors for an enhanced sedative effect could not be substantiated by our results. Peak serum levels of 61 and 53 ng/ml, respectively, for the test preparations and 40 ng/ml for the reference preparation were reached after 2.0 to 2.5 h p.a.; elimination half-lives were between 4 and 6 h. A statistically significant positive correlation could be found for AUC (0-24 h) and the amount excreted in urine in the same period of time, as higher mean serum levels were correlated with higher amounts excreted renally.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the pharmacokinetic profile of metaclazepam in old and young volunteers.

A single-centre, open, Phase I-study comparison of the pharmacokinetics of a single dose of metaclazepam 10 mg, a new 1,4-benzodiazepine has been done in 10 older and 20 younger volunteers. No important age-related effect was found on the kinetics of metaclazepam or its N-desmethyl derivative, the principal metabolite in man.

[The bioavailability and pharmacokinetics of two carbocysteine preparations after single and multiple dosing]. / Untersuchungen zur Bioverfügbarkeit und Pharmakokinetik zweier Carbocistein-Zubereitungen nach Einfach- und Mehrfachdosierung.

The relative bioavailabilities and pharmacokinetic profiles of 2 carbocisteine preparations (capsules, granulate) were evaluated in a single dose and a steady state study. 10 healthy volunteers took in a randomized, 2fold cross over design 750 mg 3-(carboxymethylthio)alanine (carbocisteine, Transbronchin) (1 portion of the granulate or 2 capsules) as a single dose or for 4 days 3 times a day (every 8 h) 1 portion of the granulate or 2 capsules, respectively. During the saturation phase the pre-dose serum levels in the morning were determined and on day 5 - after a last dosing the elimination kinetics were evaluated. The same time frame of blood withdrawals was used for the evaluation of serum kinetics after single dosing. The new developed gaschromatographic method for the rapid, sensitive and reliable quantitative determination of carbocisteine in serum saves not only a lot of time but also improves the detection limit and selectivity by a factor of approx. 10. The studies revealed bioequivalency of the carbocisteine granulate and capsule preparations. After multiple dosing, no cumulation of the carbocisteine serum levels occurred. A comparison of the AUCo-infinity and AUC tau (single/multiple dosing, respectively) showed linear pharmacokinetics without enzyme induction or saturation phenomena in man.

[Comparative studies on the tolerance of bioequivalent doses of intravenous methylxanthine preparations in healthy subjects]. / Vergleichende Untersuchungen zur Verträglichkeit bioäquivalenter Dosen intravenöser Methylxanthin-Zubereitungen bei gesunden Probanden.

In a comparative tolerance study with two different intravenous methylxanthine preparations, a theophylline-ethylendiamine preparation (TE-reference preparation) was tested against a combination of theophylline, proxyphylline (7-(2-hydroxypropyl)-theophylline) and diprophylline (7-(2,3-dihydroxypropyl)-theophylline) (Neobiphyllin; TPD = test preparation) in 10 healthy volunteers by a single blind cross-over design. Both preparations were infused under continuous control of vital parameters (blood pressure, pulse, respiration frequency, heart rhythm) as infusions (1 ampoule with 800 mg TPD or 1 short-infusion with 480 mg of TE for 20 min, each) up to the individual tolerance limit or the pre-defined limit of 3 ampoules/short infusions, respectively. The maximum tolerated infusion time and the serum levels at which the first side-effects appeared, were compared. These maximum doses could be administered to 6 volunteers under TPD, but only to two under medication with the reference preparation. Side-effects under TPD occurred in 5, after infusion of the reference preparation in 9 volunteers. Serum levels of theophylline at the end of the infusion period reached (14.6 +/- 4.21 (TPD) and 23.01 +/- 6.02 mg/l (TE), respectively. The average infusion time for the test preparation was 54.8, for the reference preparation 46.2 min. The average serum theophylline levels of the 5 volunteers with side-effects under TPD reached--when these side-effects occurred --11.26 +/- 4.52 mg/l; the same volunteers showed after administration of TE levels of 14.94 +/- 7.49 mg/l. Our results showed an approx. additive effect of the side-effects together with an--according to literature--over-additive pharmacological effect of the single components of TPD.(ABSTRACT TRUNCATED AT 250 WORDS)

[Comparative study of the bioavailability and pharmacokinetics of isosorbide dinitrate formulations in retard form and in standard preparations by determination of isosorbide-5-mononitrate]. / Vergleichende Prüfung der Bioverfügbarkeit und Pharmakokinetik von Isosorbiddinitrat-Formulierungen in Retardform gegen Standardpräparate mit Bestimmung des Isosorbid-5-Mononitrats.

The aim of the study was to determine the relative bioavailability and the pharmacokinetic parameters following administration of a slow-release formulation of isosorbide dinitrate (ISDN, Isdin) capsules (20, 40 and 60 mg). A gas chromatographic method was used to determine the plasma concentrations of ISDN and isosorbide-5-mononitrate (IS-5-MN). All of the required pharmacokinetic parameters were ascertained. The study was performed on 12 healthy volunteers in a steady-state crossover design. A comparison of the areas under the plasma concentration/time curves of the test preparations and the commercial preparations showed higher values for the test preparations in all of the investigations. However, these values were only statistically significant for the 40 and 60 mg formulations ISDN and the 60 mg formulation IS-5-MN.

Quantitative determination of bencyclane in human plasma by capillary gas chromatography/chemical ionization mass spectrometry.

Since 10 years there is a phenomenal increase in the use of mass spectrometry, combined with (capillary-) gas chromatography and dedicated data systems for the rapid, reliable, sensitive and selective determination of xenobiotics (drugs, their degradation/biotransformation products etc.) in biological fluids. This applies especially since the introduction of newer developments in ionization techniques (CI, DCI, FAB) and gas chromatographic column technology (fused silica, bonded phase columns). We employed such a sophisticated method for the quantitative determination of N-[3-(1-benzyl-cycloheptyl-oxy)-propoxy]-N,N'- dimethylammoniumhydrogen fumarate (bencyclane) in human plasma after oral application of a therapeutic doses. Our results clearly show that this approach is the best method available; furthermore the detected plasma levels will lead to discussions with respect to the pharmacokinetic properties of the drug.

Quantitative determination of diphenhydramine and orphenadrine in human serum by capillary gas chromatography.

Diphenhydramine has been in medical use for 35 years as an antihistamine and hypnotic. We evaluated the pharmacokinetic parameters, which are not only important for disposition studies, in the serum of 10 volunteers who received a single dose of 31 mg diphenhydramine. For this purpose a suitable capillary GC-method was developed, which has a detection limit of 2 micrograms/l (serum); the calibration curve is linear between 2.5 and 120 micrograms/l, the reproducibility is always better than 3.6% and the average recovery is about 100.1%. The combination of a relatively non-polar extraction solvent, a selective detector (N-FID) and a fused silica, bonded-phase capillary column led to a more rapid sample clean-up procedure (no back-extraction needed) and is sensitive and specific enough for the quantitative determination of diphenhydramine, orphenadrine or other ethanolamines in human serum.

[Mass spectrometric data on some drugs, their biotransformation products and intermediate products of illegal synthesized narcotics]. / Die massenspektrometrischen Kenndaten einiger Arzneistoffe, deren Biotransformationsprodukte sowie der Zwischenprodukte illegaler Rauschgiftsynthesen.

Additional mass spectral data of some rather unusual drugs and their biotransformation-products are presented updating the three large and authoritative mass spectra data collections for forensic/clinical toxicological purposes published by Finkle, Foltz and Saferstein et al. Furthermore mass-spectra data of chemicals, intermediates, by-products and final products of illegal drug syntheses are summarized in one chapter.

[Bioavailability of glycerol trinitrate (nitroglycerin) from an ointment preparation]. / Bioverfügbarkeit von Glyceroltrinitrat (Nitroglycerin) aus einer Salbenzubereitung.

After application of an ointment of glycerol trinitrate (nitroglycerin, Nitrofortin; in the following briefly called GTN) the bioavailability of the unchanged GTN was evaluated. For that purpose a gas chromatographic/mass spectrometric method was employed, the only method which guarantees the selectivity and sensitivity necessary for this kind of studies. In this respect selectivity means that only the unchanged drug is determined and degradation and/or biotransformation products are measured only if needed. Considering the well-known tremendous inter-individual variations, which are quite common in studies with this compound, and the associated problems of getting statistically relevant data the study was performed on 12 volunteers. Detectable GTN-levels were obtained up to 48 h after application, maximum plasma levels (836.1 +/- 124.2 pg/ml) were reached after 1.37 +/- 1.55 h. 12 h after application plasma concentrations of 154 +/- 20 pg/ml were observed which decreased to 65 +/- 13 pg/ml after 24 h.

[Analysis and renal excretion of pirisudanol (Stivane)]. / Zur Analytik und renalem Ausscheidungsverhalten von Pirisudanol (Stivane).

The chromatographic and spectroscopic properties (TLC; UV; IR; 1H-NMR; GC/MS) of the psychostimulant Stivane (dimaleate;I) are presented in detail, describing some analytic peculiarities of the pure substance as well. Moreover, the results of the renal excretion studies are reported: after hydrolysis in each of the acidic and basic urine extracts a degradation product--but no unchanged drug--could be detected.

[Comparative studies on the in vitro dissolution and bioavailability of various acetylsalicylic acid preparations]. / Vergleichende Untersuchungen zur In-vitro-Freisetzung und Bioverfügbarkeit von verschiedenen Acetylsalicylsäure-Fertigarzneimitteln.

For five different brands of acetylsalicylic acid (ASA) preparations the in vitro/in vivo data were determined and tested for comparability. The in vitro dissolution rates were determined by two different methods (Paddle, rotating basket) whereas the in vivo data were obtained from 15 volunteers in a 5-fold cross-over trial. The markedly worse in vitro dissolution (rotating basket) of one preparation is in contrast to the in vivo data which showed bioequivalency of all five preparations. It is doubled that in vitro measurements alone reveal sufficient informations for any predictions of the in vivo characteristics (e.g. bioavailability) of a preparation. It was possible to determine separately ASA and salicylic acid using a highly selective HPLC-method developed by us.

[Gas chromatographic/mass spectrometric determinations of indomethacin serum levels in the course of pharmacokinetic studies in healthy volunteers]. / Die gaschromatographisch/massenspektrometrische Bestimmung der Indometacin-Serumspiegel im Verlauf pharmakokinetischer Untersuchungen an gesunden Freiwilligen.

For 4 different brands of indomethacin preparations the in vitro dissolution data as well as their relative bioavailabilities were determined. The in vitro tests were performed by the rotating basket method; the quantitative determinations of the serum-levels were determined by an gas chromatographic/mass spectrometric assay employing registration of the characteristic selected ion current profiles of the compound. Furthermore a special method for synthesis of the needed internal standard was also developed. The in-vivo-studies - with 15 volunteers in a 4 fold crossover-showed - in contrast to the worse in-vitro-dissolution of one preparation - bioequivalency of all four preparations. Our results clearly show that statements on in-vitro/in-vivo correlations have to be cautious.