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  • 1
    Electronic Resource
    Electronic Resource
    Mean time and first-pass metabolism (1985)
    Springer
    European journal of clinical pharmacology 29 (1985), S. 45-48 
    Details
    ISSN: 1432-1041
    Keywords: molsidomine ; nortryptiline ; propranolol ; mean time ; first-pass effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The theoretical principles are outlined for estimating the fraction of a drug undergoing first-pass metabolism using only the plasma levels found after a single oral dose. Data for 3 drugs are used to illustrate the method. It involves analysis of the parent drug and the metabolite formed during the first passage through the gut wall and liver and evaluation of their total mean times. The mean time characteristics of molsidomine, nortriptyline and propranolol are considered and they confirm the theoretically deduced dependency of the mean time of the parent drug and the metabolite. Whether the results are more precise than those obtained from comparison of areas after oral and intravenous administration is discussed. From the data presented it is clear that the mean time method depends on the scatter inherent in the data. In order to estimate the true first-pass effect, greater scatter requires an increased number of data pairs, i.e. subjects. If intravenous data are not available, however, the method described provides a rough but worthwhile estimate of the first pass effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00547367
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  • 2
    Electronic Resource
    Electronic Resource
    Penbutolol: Pharmacokinetics, effect on exercise tachycardia, and in vitro inhibition of radioligand binding (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 613-623 
    Details
    ISSN: 1432-1041
    Keywords: penbutolol ; beta-adrenoceptor blockade ; pharmacokinetics ; pharmacodynamics ; in vitro/in vivo correlation ; radioreceptor assay ; active metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of penbutolol 40 mg, its reduction in exercise-induced tachycardia, and the in vitro inhibition of radioligand binding to beta-adrenoceptors by plasma have been investigated in 7 healthy volunteers. The peak penbutolol concentration of 285 ng/ml was observed 1.2 h after administration, and the maximum of 4′-OH-penbutolol of 4.76 ng/ml was found after 1.64 h. Penbutolol was detected for up to 48 h, and 4′-OH-penbutolol dropped below the limit of detection after about 10 h. The terminal plasma concentration of penbutolol declined with an average half-life of 19 h. The maximum reduction in exercise-induced tachycardia was 33 beats/min 2.6 h after taking penbutolol. There was still a significant reduction of about 7 beats/min after 48 h. This effect could be adequately explained by the concentration-time course of penbutolol in combination with Clark's model of the concentration-effect relationship. Antagonist activity in plasma caused 91% inhibition of radioligand binding in vitro to beta2-adrenoceptors on rat reticulocyte membranes 1.6 h after intake of penbutolol. By 48 h after intake, radioligand binding was still significantly inhibited (23%). The in vitro inhibition of radioligand binding by plasma showed a linear correlation with the reduction in exercise-induced tachycardia for all phases of the workload. The time course of the reduction in heart rate was completely explained by the in vitro inhibition of radioligand binding. However, it was not possible to explain the in vitro inhibition of radioligand binding by the concentration-time course of penbutolol using a simple competition model, although both variables were based on the same sampling site. When the in vitro inhibition of radioligand binding was plotted against the penbutolol concentration at the same sampling times (with both variables transformed to multiples of the apparent inhibition constant) the discrepancy became even more apparent as time-related counterclockwise hysteresis. None of the known metabolites of penbutolol can explain the discrepancy between the penbutolol concentration and the inhibition of radioligand binding in vitro. It appears that an other active metabolite is formed, which contributes to the effect in vitro and in vivo and so can explain the observed discrepancy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637597
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  • 3
    Electronic Resource
    Electronic Resource
    Estimating reduced availability due to first pass elimination from relative total clearance and renal clearance (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 397-400 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; bioavailability estimate ; oral clearance ; first-pass effect ; renal clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A simple formula is presented for estimating the systemic availability of an orally administered drug from the relative total clearance (oral clearance) when renal clearance forms an important part of total clearance. Hepatic plasma flow is used in the equation and is represented by an average value taken from the literature. The formula is applied to data for cimetidine discussed in the literature. A further application is demonstrated for a drug under development for which an intravenous formulation was not available. It is possible to estimate the upper and lower limit of availability if some information on the amount of drug absorbed is available.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561371
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  • 4
    Electronic Resource
    Electronic Resource
    Characterization of cyclosporine a uptake in human erythrocytes (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 417-419 
    Details
    ISSN: 1432-1041
    Keywords: Cyclosporine A ; uptake ; human erythrocytes ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract More than 70% of cyclosporine A (CsA) is bound to erythrocytes at whole blood concentrations of 50–1000 ng·ml−1. Cytosolic CsA is bound to the erythrocyte peptidyl-prolyl cis-trans isomerase cyclophilin. Measurements of serum CsA levels under clinical conditions are hampered by a temperature-dependent translocation of CsA into erythrocytes during cooling of the probes to room temperature. In order to characterize the kinetics of CsA uptake and to find a specific uptake inhibitor, we developed a method to measure the velocity of uptake based on rapid cooling of the erythrocyte suspension. The total erythrocyte-binding capacity for CsA amounted to 43·10−5 nmol per 106 erythrocytes or 2.6·105 molecules per erythrocyte. Whereas the erythrocyte-binding capacity of CsA was temperature-independent between 10°C and 42°C, uptake kinetics of CsA were temperature-dependent. The Arrhenius plot for CsA uptake in human erythrocytes was linear and no transition temperature between 0°C and 42°C could be detected. Therefore the CsA uptake process in human erythrocytes did not fulfil the criteria of carrier-mediated transport. This indicates that CsA diffuses passively into human erythrocytes. Hence, erythrocyte CsA uptake cannot be specifically inhibited.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00191903
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  • 5
    Electronic Resource
    Electronic Resource
    A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers (1998)
    Springer
    European journal of clinical pharmacology 53 (1998), S. 361-367 
    Details
    ISSN: 1432-1041
    Keywords: Key words Caffeine metabolism ; Cigarette smokers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To analyse distributions of a urinary ratio of caffeine metabolites (MRc) representative of cytochrome P450 (CYP) 1A2 activity in a cohort of Caucasian German healthy volunteers and to re-assess the effects of smoking and oral contraceptives on the range and type of MRc distribution. Methods: A cohort of volunteers comprising 192 individuals (96 males, 96 females) was divided into subgroups according to smoking and/or use of oral contraceptives. The CYP1A2 substrate caffeine was administered, and urine was collected for 6 h and analysed for representative caffeine metabolites. Distribution of a CYP1A2-dependent MRc was analysed using cumulative distribution (probit) plots and Rosin-Rammler-Sperling-Weibull (RRSW) functions. Results: Cumulative distribution curves for males, and females, without further subgrouping for smoking habits and/or oral contraceptive steroid (OCS) consumption, showed slightly higher MRc values, i.e. slightly higher CYP1A2 activities, in males. Significantly higher MRc values were found in smokers of both sexes than in non-smokers. The distributions among female non-smokers or smokers with and without OCS were nearly superimposible, however. For the two male subgroups, the sum of two RRSW functions resulted in a better adjustment to the data than a unimodal skewed distribution. A weak correlation between MRc and the number of cigarettes smoked per day was found. Conclusion: The inducing effect of smoking on CYP1A2 activity was confirmed, whereas no significant inhibitory effect of oral contraceptives was observed. The finding that the data are compatible with bimodal distributions in non-smokers suggests a significant impact of genetic factors on MRc. Among smokers, data were also compatible with bimodal distributions, i.e. with the existence of a “non-responder” phenotype concerning CYP1A2 induction by compounds present in tobacco smoke.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050394
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  • 6
    Electronic Resource
    Electronic Resource
    A rotating iterative procedure (RIP) for estimating hybrid constants in multi-compartment analysis on desk computers (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 381-388 
    Details
    ISSN: 1432-1041
    Keywords: Pharmacokinetics ; curve fitting program ; desk computer ; Gauss-Newton ; non-linear least squares fitting
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Therotatingiterativeprocedure (RIP) is a programming concept for non-linear least squares fitting of multiexponential equations to experimental data in pharmacokinetics. The method is economical in its use of program and active register capacity and can be employed in modern electronic desk-top computers. The algorithms necessary for obtaining primary estimates of various logarithmic components and their subsequent correction are presented, with as little higher mathematics as appeared permissible. The procedure is described in the sequence that would actually be followed in a pharmacokinetic analysis, and an example is included, as well as a skeleton version of a program written in BASIC. Some instructions for obtaining overall statistical parameters are given.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00566536
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  • 7
    Electronic Resource
    Electronic Resource
    In vitro — In vivo correlation of dissolution, a time scaling problem? Transformation of in vitro results to the in vivo situation, using theophylline as a practical example (1985)
    Springer
    European journal of clinical pharmacology 28 (1985), S. 291-300 
    Details
    ISSN: 1432-1041
    Keywords: drug dissolution ; theophylline ; in vitro/in vivo correlation ; convolution ; deconvolution ; in vitro/in vivo dissolution ; slow-release formulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two principal approaches to demonstrating the continuous in vivo relevance of an in vitro dissolution test are outlined. The first uses the convolution technique to predict the concentration-time course in vivo; the second uses deconvolution as a mathematical tool to estimate the in vivo dissolution profile. The weighting function must be known to utilise either technique. Defined by the aim of the analysis the dose-normalized response to the oral solution is regarded as the weighting function (Impulse Response). In both cases the essential step is continuous comparison of the predicted time dependent data with actual readings of the same class. To permit the prediction of concentration-time data from in vitro dissolution data the basic equations for the transformation of the time base from in vitro to in vivo conditions are developed. The transformation is essential, since one cannot assume that the time scales for the in vitro and the in vivo experiment are definitely the same. The estimated in vivo dissolution profile using the deconvolution technique gives a hypothetical image of the true in vivo dissolution curve. Comparison with in vitro dissolution test results, using one of the equivalence testing procedures, reveals how closely and for how long the in vitro dissolution test simulates the in vivo dissolution process. For the formulation of theophylline studied, equivalence of the in vitro and the estimated in vivo dissolution profiles was not confirmed for the entire period of observation, but it was demonstrated for approximately the first 5 h. The later inequivalence is not due to possible non-linear or time-dependent kinetics of theophylline. There is a discussion of whether a change in pH, agitation of the formulation, diffusion conditions or the absorption rate constant along the gastrointestinal tract might explain the biphasic linear correlation of the in vitro and in vivo data observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543326
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  • 8
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of an extended-release dosage form of molsidomine in patients with coronary heart disease (1985)
    Springer
    European journal of clinical pharmacology 28 (1985), S. 611-613 
    Details
    ISSN: 1432-1041
    Keywords: molsidomine ; angina pectoris ; pharmacokinetics ; molsidomine retard
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester; Cassella-Riedel Pharma GmbH, Frankfurt/M. FRG) has an antianginal effect for up to 3–5 h after oral administration of 2 mg Corvaton [1]. Plasma levels of the parent drug can be measured during this interval. A new galenic formulation (Corvaton retard) has been developed to prolong the duration of the therapeutic action and to improve patient compliance. The present study was carried out to establish whether the in vitro dissolution profile of the tablet was reflected in vivo, thus permitting prediction of plasma molsidomine levels in patients with coronary heart disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544076
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  • 9
    Electronic Resource
    Electronic Resource
    Absorption of glibenclamide from different sites of the gastro-intestinal tract (1985)
    Springer
    European journal of clinical pharmacology 29 (1985), S. 193-197 
    Details
    ISSN: 1432-1041
    Keywords: Glibenclamide ; intestinal absorption ; small and large intestine ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a study of eight volunteers and six patients, glibenclamide was placed at different sites of the gastro-intestinal tract under visual control. The dose was instilled once into the stomach and once into the duodenum of the eight volunteers in a randomized crossover design. The six patients underwent diagnostic colonoscopy, and the dose was placed into the ascending colon if pathological findings were not present. The area under the concentration-time curve, completed by extrapolation, and the mean residence time of the drug in the body were calculated. These pharmacokinetic characteristics were examined using a Jonckheere test for ordered alternatives and a Wilcoxon signed rank pair test. The means of the areas under the curve were 477±131 ng·h ml−1 for the stomach, 475±142 ng·h ml−1 for the duodenum and 486±301 ng·h ml−1 for the colon. The mean residence time changed from 2.67±0.35 h for the stomach to 2.42±0.48 h for the duodenum and 3.55±0.68 h for the colon. These results indicate that although glibenclamide is absorbed from all three sites of the gastro-intestinal tract to the same extent, the rates of absorption are different. It is discussed whether these findings really confirm the pH-partition hypothesis in drug absorption. Since glibenclamide — a weak acid — has a pK-value of about 6.5, these data seem to confirm the pH-partition hypothesis of drug absorption.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00547421
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  • 10
    Electronic Resource
    Electronic Resource
    The absorption of piretanide from the gastro-intestinal tract is site-dependent (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 79-82 
    Details
    ISSN: 1432-1041
    Keywords: piretanide ; gastro-intestinal absorption ; mean absorption time ; stomach ; duodenum ; colon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of piretanide was investigated after placing the drug in the stomach, duodenum and ascending colon under visual control. The relative amounts absorbed and the rates of absorption were estimated from the area under the curve and the total mean time, respectively. Similar amounts of piretanide were absorbed and at almost the same rate after placement in the stomach and duodenum; the area under the curve for the stomach was 250 ng h/ml and for the duodenum 243 ng h/ml, the mean absorption times being 1.97 h and 1.51 h respectively. A marked difference was observed in the rate of from the ascending colon; the area amounted to 66 ng h/ml and the mean time to 3.99 h. Although area values for the colon were significantly different from those observed with the stomach and duodenum, it must be emphasised that the amount absorbed depends on the time the drug is in contact with the absorbing surface. There is discussion of whether the differences in absorption between the duodenum and colon can be explained by the physico-chemical properties of the drug alone, or whether the results reflect a saturable transport mechanism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614200
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