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A novel slow release preparation containing 24 mg molsidomine has been investigated in 6 healthy subjects. Individual concentration/time-profiles after the tablet showed two separate concentration peaks at 2.2 h and 15.0 h. The relative bioavailability of the slow release preparation in comparison to an aqueous solution of molsidomine was 0.67. The in vivo dissolution profile revealed either a progressive decrease in dissolution velocity caused by altered physico-chemical conditions in the ileum and the colon or a progressive reduction in the absorption constant. In all subjects deconvolution revealed a punctual increase in absorption about 15 h post-dose, coinciding with the second peak of the concentration/time-profile. Therapeutic plasma levels of molsidomine (greater than 5 ng.ml-1) were not maintained over 24 h by this slow release formulation.

Ramipril was administered to 13 patients, aged 49-80 years, weighing 53,5-90,3 kg, with congestive heart failure (CHF) for 2 weeks in an open trial. One patient dropped out after day 1 and another accidentally received another angiotensin-converting enzyme (ACE) inhibitor, so that 11 patients remained for 'analysis. Each patient received 5 mg of ramipril daily for 2 weeks, followed by a 1-week washout period. Urine was collected in 4-h fractions for 12 h followed by a 12-h fraction on days 1, 8, and 15

Objective Sildenafil may provide an effective treatment for erectile dysfunction, frequently observed in uremic patients and after kidney transplantation. Pharmacokinetic interactions between sildenafil and tacrolimus are to be expected due to a common elimination pathway via cytochrome P450 3A4. Therefore, the pharmacokinetics during combined use of these agents were studied over 9 days. Material and methods Nine male patients (age 29-52 years) were included, who had previously participated in a recent interaction study with sildenafil given as a single dose. Comedication remained unchanged in order to avoid introducing confounding factors. In the previous study in the patients, tacrolimus blood levels with and without sildenafil were measured for pharmacokinetic analysis. In the present study, 25 mg sildenafil were coadministered daily over 9 days and tacrolimus levels were assessed at sampling times optimized using simulation. In addition, laboratory parameters and blood pressure changes were measured and adverse effects monitored. Results Terminal half-lives of tacrolimus did not differ significantly and trough levels did not change when sildenafil was coadministered daily over 9 days. Mean arterial blood pressure was lower after sildenafil intake. Two patients had to reduce their antihypertensive treatment, 6 patients reported mild side effects. In 1 case, there was an asymptomatic, temporary increase in the serum concentration of gamma-GT. Conclusions There was no evidence obtained for a change in elimination half-life or average concentration of tacrolimus during repeated coadministration of sildenafil. Since blood pressure decreased, a starting dose of 25 mg sildenafil and, if necessary, adjustment of the dose of antihypertensive drugs on days when sildenafil is given has to be considered. With respect to the observed blood pressure changes, pharmacokinetic/pharmacodynamic interaction studies with other antihypertensive drugs are of critical importance in these patients.

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 x 10(-5) nmol per 10(6) erythrocytes or 2.6 x 10(5) molecules per erythrocyte. Whereas the erythrocyte-binding capacity of CsA was temperature-independent between 10 degrees C and 42 degrees 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 degree C and 42 degrees 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.

In 1958, F.H. Dost [1958] defined the mean life-span ("mittlere Lebensdauer") of a total number of N molecules as the arithmetic mean of all times "z(i)" of any one of the N molecules residing in a pharmacokinetic system. This pharmacokinetic characteristic did not attract special interest for several years. Almost simultaneously Yamaoka et al. [1978], Cutler [1978], van Rossum [1978], Benet and Galeazzi [1979], and von Hattingberg and Brockmeier [1979] recommended the mean residence time (MRT) or mean time (MT) as a useful summarizing characteristic for complex pharmacokinetic systems. One of the most useful properties of the statistical analysis (also called "moment analysis" or "statistical moment analysis") of concentration-time data and in vitro dissolution profiles using moments is the additivity of mean times [von Hattingberg and Brockmeier 1978, 1979]. The very simple and compelling logic of additivity can be explained by the following example: considering an oral administration of a readily available dosage form, the distribution of each individual molecule within the body and the elimination from the body must be preceded by absorption of this molecule, which is trivial. However, as a consequence, the total transit time of an individual molecule through this system is the sum of its time up to absorption into the central circulation z(i).abs and the time the molecule spends in any part of the volume the molecule can reach z(i).vss. Therefore, the total mean time of all drug molecules available is the sum of the mean absorption time MT(abs) and the mean time in the steady-state volume of distribution MTvss. It is obvious that we can estimate the two components of the total mean time, i.e. MTabs and MTvss, by an appropriate experimental setting giving the drug once intravenously and determining MTvss and once giving the drug as an oral solution and deducing MTabs = MTtotal - MTvss. Because of this very useful property of the statistical analysis of concentration-time data by moments, this approach has been entitled "component analysis" [von Hattingberg et al. 1984].

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.

The pharmacokinetics of angiotensin converting enzyme (ACE) inhibitors are often difficult to characterize using standard tools. Most of the problems arise from the tight binding of ACE inhibitors to ACE. The present paper discusses how tight binding of ramiprilat to ACE affects the pharmacokinetic characteristics and in vitro measurement of ACE inhibition. Data from a randomized crossover study in healthy volunteers given 2 different dosage forms with 5 mg ramipril serve to compare the theoretically deduced predictions with actual measurements. The data confirm that elimination is concentration-dependent and that therefore the pharmacokinetics are non-linear. Renal clearance increases with concentration. With respect to pharmacodynamics, free ramiprilat depletion due to tight binding is the reason for the steep nature of concentration-effect curves often observed for ACE inhibition. This type of relationship, however, cannot be described by the classical Emax model nor by the sigmoid Emax model. The model of tight binding presented shows that the concentration-effect curve becomes steeper the larger the concentration of ACE and the greater the affinity of the inhibitor to the target molecule. With the classical Emax model the concentration can be doubled about 3 times to increase the measurable effect from 10 to 50% maximum effect, and because the relationship is symmetric at the EC50% point of inflection, the concentration can be doubled another 3 times to increase the effect from 50 to 90%. With the tight-binding concentration-effect relationship, doubling the concentration about 3 times may also increase the effect from 10 to 50% of the maximum effect, a further doubling of the dose, however, causes a steep increase of the effect from 50 to nearly 100%. This tight-binding concentration-effect relationship may also be present in other classes of drugs.

Human blood platelets contain high levels of non-receptor protein tyrosine kinases of the Src family, particularly pp60c-src, suggesting an important role for these enzymes in platelet physiology. Indeed, in response to various agonists of platelet function, a number of proteins become phosphorylated at tyrosine residues. However, no enzymic activation of an Src-related tyrosine kinase has yet been shown in platelets. In searching for the kinase(s) responsible, we found that all agonists tested that directly or indirectly activate protein kinase C in platelets (phorbol 12-myristate, 13-acetate, thrombin, vasopressin, collagen, calcium ionophore A23187) increased the overall activity of pp60c-src determined by IgG phosphorylation in an immunocomplex assay in the presence of low ATP concentrations. On the other hand, elevation of cyclic AMP directly by forskolin or indirectly by prostaglandin E1, or elevation of cyclic GMP by sodium nitroprusside did not significantly affect the activity of the enzyme. To substantiate the differences in enzyme activity, we determined Km and Vmax, values of pp60c-src from resting and thrombin-stimulated platelets. Thrombin treatment increased substrate affinity of pp60c-src as indicated by a 2- to 3-fold decrease in the Km values for ATP and the exogenous protein substrate casein. Vmax. values were only slightly altered under the assay conditions used. To further rule out modifications of pp60c-src in phosphorylation as a probable cause of the changed substrate affinity, we analysed tryptic phosphopeptides of immunoprecipitated, 32P-labelled pp60c-src of unstimulated and stimulated platelets. The platelet agonists listed above induced an increase in pp60c-src phosphorylation at Ser-12, which is the amino acid phosphorylated by protein kinase C. Surprisingly, we found that elevation of cyclic AMP did not affect 32P labelling of pp60c-src. On the basis of our data, we suggest that phosphorylation at Ser-12 might be one of the signal-triggering events that cause the increase in substrate affinity of pp60c-src.

Thirteen patients with chronic congestive heart failure of NYHA class II-III received multiple doses (14 days) of ramipril (5 mg once daily); the concentrations of ramipril and ramiprilat in plasma, as well as ramipril, ramiprilat, glucuronides, diketopiperazine, and diketopiperazine acid in urine were measured at various times for 14 days. One patient dropped out after the first day due to hypotension and another who accidentally received another ACE inhibitor additionally was excluded, so that 11 patients completed the study. Ramipril and ramiprilat in plasma were determined by radioimmunoassay, and ramipril and its metabolites in urine were measured by gas chromatography in the laboratories of Hoechst AG. Peak concentrations of the active substance ramiprilat were reached after about 4 h and amounted to 22.3 +/- 11.1 ng/ml after the first dose, and a peak concentration of 26.6 +/- 10.0 ng/ml was observed 2.5 +/- 1.4 h on average after administration on day 14. Practically no accumulation was observed for ramiprilat; the AUD (0-24 h) values increased from 191.3 +/- 83.1 ng.h/ml for the first study day to 238.3 +/- 98.0 ng.h/ml for day 14. As expected, only very small fractions of the dose were excreted with urine as unchanged ramipril and ramipril glucuronide. Ramiprilat is excreted with urine to a larger extent than is rampiril--on average 6.6 +/- 3.0% on the first day and 12.2 +/- 3.8% on day 14. The total amount excreted increased by 34% on average, and was mainly due to an increased ramiprilat excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of cefodizime (CDZ) were determined after i.v. and i.m. administration of single doses of up to 2 g and after i.v. administration of 2 g b.i.d. for six days. Serum concentrations were adequately described by three exponential functions, with a terminal half-life of about 4 h. Serum and urine levels and amounts excreted were dose-proportional, and derived pharmacokinetic characteristics were dose-independent. Steady state was established after the second dose (b.i.d.). CDZ is 100% bioavailable after i.m. administration. Concomitant administration of lidocaine did not alter either bioavailability or pharmacokinetic characteristics. Following administration of 1 and 2 g i.m., Cmax was reached after 1.2 h and amounted to 60 and 140 mg/l, respectively. CDZ is 88% bound to plasma proteins. CDZ was predominantly eliminated by the kidneys (80% of dose), a further 20% being excreted in the bile. Metabolites were not detectable in serum or urine. Dose adjustment does not seem warranted in the elderly. For renally impaired patients with CLcr between 30 and 10 ml/min, the daily dose should not exceed 2 g. For patients with CLcr below 10 ml/min, individual adjustment is suggested. CDZ showed good penetration into tissues and biological fluids (lung, bronchial secretions, pleural fluid, kidney, prostate, urine, bone, muscle, skin, Fallopian tube) with long-lasting concentrations. In urine, therapeutic concentrations were present for more than 24 h after administration of 1 and 2 g. Thus, on the basis of its pharmacokinetic profile, cefodizime is appropriate for effective treatment with once-daily administration.

In an open trial 5 mg ramipril daily for 2 weeks was administered to 11 patients with congestive heart failure. 24-hour plasma profiles of atrial natriuretic peptide (ANP), antidiuretic hormone (ADH), angiotensin II (Ang II) and aldosterone (Aldo) were determined before and on days 1 and 15 of ramipril treatment, respectively. Urinary sodium excretion was also measured at the same time points. There were no relevant differences in the 24-hour profiles of ANP and ADH. Ang II values dropped as expected on the first day of ramipril treatment from 11.2 pg/ml to 2.9 pg/ml at 3 h post administration and from 6.7 pg/ml (predose) to 1.8 pg/ml at 2 h post administration on day 15. Plasma aldosterone values increased slightly from day 1 to day 15, sodium excretion increased from 125.9 mmol to 166.5 mmol/24 h; however, both changes in the 24-hour profiles were nonsignificant. A clinically relevant improvement in the severity of CHF was observed. From a total of 121 reported symptoms according to McKee et al., 35 showed an improvement; 81 remained unchanged, in only 5 symptoms a deterioration was observed. According to the NYHA-classification 5 patients improved from grade III to II, 6 remained unchanged.ACE inhibition does not induce changes in ANP or ADH levels in the resting state while Ang II decreases. A slight increase in aldosterone levels may be due to increased sodium excretion.

Ramipril was administered to 13 patients, aged 49-80 years, weighing 53.5-90.3 kg, with congestive heart failure (CHF) for 2 weeks in an open trial. One patient dropped out after day 1 and another accidentally received another angiotensin-converting enzyme (ACE) inhibitor, so that 11 patients remained for analysis. Each patient received 5 mg of ramipril daily for 2 weeks, followed by a 1-week washout period. Urine was collected in 4-h fractions for 12 h followed by a 12-h fraction on days 1, 8, and 15. Creatinine clearance, as well as the excretion of albumin and the urinary brush border enzymes gamma-glutamyl transferase (GGT), alanine aminopeptidase (AAP), N-acetyl-beta-D-glucosaminidase (NAG), and lactate dehydrogenase (LDH) were determined. The values for albumin excretion, creatinine clearance, GGT, AAP, NAG, and LDH obtained for the various days during the time course before and during multiple dosing were subjected to an analysis of variance followed by Scheffe's test for means. Daily albumin excretion decreased during treatment with ramipril from 23.8 +/- 27.4 mg/24 h (baseline) to 12.9 +/- 15.1 (day 1), 10.8 +/- 15.6 (day 8), and 12.4 +/- 12.7 mg/24 h (day 15). The differences were significant (alpha = 0.05) when compared to pretreatment albumin excretion. Creatinine clearance increased from 78.8 +/- 38.3 ml/min (baseline) to 82.4 +/- 34.6 (day 1), 85.1 +/- 28.5 (day 8), and 91.7 +/- 36.4 ml/min (day 15). The change on day 15 was significant (alpha = 0.05) when compared to pretreatment values.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of racemic prenylamine were investigated in 6 healthy volunteers. Plasma levels were determined by gas chromatography/mass spectrometry. Concentration-time profiles were analyzed both by compartment-dependent and compartment-independent pharmacokinetic models. Terminal elimination half-life was 14.1 h (SD: 6.9 h). The apparent total clearance was 5.8 l/min. Mean residence time of racemic prenylamine was found to be 14.7 h (SD: 3.8 h). The relative bioavailability of prenylamine (Segontin 100) was 82.2% (SD: 9.9%) determined in six healthy volunteers. The volunteers received simultaneously the film tablet and 100 mg racemic dideuteroprenylamine as an aqueous solution of the lactate. This procedure is known to exclude intraindividual changes in absorption, first-pass metabolism or volume of distribution that might occur on sequential administration. The absolute bioavailability was estimated to be in the order of 15%. In a pilot study the pharmacokinetics of the enantiomers were investigated in 2 healthy volunteers. S-(+)-prenylamine was eliminated considerably faster from plasma than R-(-)-prenylamine suggesting a stereoselective metabolism. The AUC of the (+)-enantiomer was 20% of that of the R-(-)-prenylamine.

The pharmacokinetics of a single oral dose of roxatidine acetate 150mg were studied in 31 patients with varying degrees of chronic renal failure. The patients were divided into 5 groups according to their creatinine clearance (Clcr): controls (Clcr 94.5 ± 13.9 ml/min; n=6); mild chronic renal failure (Clcr 47 ± 6 ml/min; n=4); moderate chronic renal failure (Clcr 27.3 ± 3.1 ml/min; n=4); severe chronic renal failure (Clcr 12.8 ±1.4 ml/ min; n=5) and uraemia (Clcr 6.6 ± 0.6 ml/min; n=12).

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.

In this paper the effects of chronic renal failure on the pharmacokinetics of H2-antagonists are reviewed and the results obtained with roxatidine presented. In normal renal function renal clearance is around 60-80% of total plasma clearance of all H2-antagonists. Consequently, prolongation of serum half-life, mainly due to a decrease in urinary excretion, is noted in patients with decreasing glomerular filtration rate. In chronic renal failure, a dose reduction is therefore necessary with all H2-antagonists, including roxatidine. It appears that neither haemodialysis nor peritoneal dialysis substantially influences the pharmacokinetics of these drugs. Therefore, the same dosage schedule as in uraemia may be applied in patients with dialysis. Finally, in the elderly the dosage of all H2-antagonists should be adapted to the expected decrease in renal function.

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.

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.

To study the fundamental differences between agonist and antagonist interaction with the β-adrenoceptor of the rat reticulocyte the radiolabeled agonist3H hydroxybenzylisoprenaline (3H HBI) and the radiolabeled antagonist3H dihydroalprenolol (3H DHA) were used. Equilibrium binding experiments with3H HBI revealed all characteristics expected to a β-adrenoceptor site, i. e. high affinity binding (K D high=7.4±0.9×10−9 M), saturability (B max high=230±24 fmoles/mg protein), and stereoselectivity. The rank order of potency for competing agonists was isoprenaline > adrenaline > noradrenaline > dopamine.3H HBI high affinity binding sites amounted to about 25% of β-adrenoceptor sites detectable with3H DHA. In competition experiments with3H HBI and (-)isoprenaline[(-)Ipn]aK D high-value for (-)Ipn of 3.1±0.6×10−8M was obtained corresponding to theK D high-value of (-)Ipn obtained from competition experiments using3H DHA. For (-)propranololK D-values of 0.9±0.5×10−8 M and 1.0 ±1.0×10−8 M were measured using3H HBI and3H DHA respectively. Agonist affinity derived from competition experiments with (-)Ipn versus3H DHA was not affected by temperature changes. Guanylyl-imidodiphosphate [Gpp(NH)p] decreased concentration dependently the number of high affinity binding sites of3H HBI not affecting the respectiveK D-value. Similar effects were observed after omission of Mg2+ from the binding assay or inclusion of Na+ in the Mg2+-free incubation mixture. The association reaction of3H HBI at the β-adrenoceptor revealed two different velocities. The slower phase of the association reaction which represents high affinity binding (80% of equilibrium binding) is not observed in the presence of Gpp(NH)p. A biphasic dissociation of3H HBI binding was induced by 10−4 M (±)propranolol: 25% dissociated with at 1/2 of 1.3 min whereas the high affinity binding was reversed with at 1/2 of 150 min. This slowly reversible binding of3H HBI however was rapidly reversed by Gpp(NH)p (t 1/2

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.

The Mean Time—mittlere Verweildauer—as defined by Dost [3] is the statistical mean of all particular times any individual molecule of a dose is held up within a pharmacokinetic system prior to being eliminated from it. It is demonstrated that this mean time is as model independent as Dost’s rule of areas. Operational algorithms for its assessment are presented. It can be used to characterize the time dependencies of a drugs “in vivo dissolution” from in vitro measurements. This is possible, since in a model consisting of a chain of, although undefined, subsystems, the mean Time in the model is the algebraic sum of all mean Times attributable to such subsystems. This linear relationship between in vitro and in vivo mean Times is found valid for different pharmaceutical formulations of carbocromene-HCI.

The influence of drug bioavailability on therapeutic regimens has increased the interest in in vitro dissolution testing and the quantitative interpretation of dissolution profiles. The mean and variance of in vitro dissolution times are appropriate parameters for discriminating different dissolution profiles. This article demonstrates that both parameters can easily and immediately be derived from dissolution data. Moreover, it is shown that the mean and variance of in vitro dissolution times define the parameters which appear in the model equation of a linear transport process. This model equation is proved to be valid for five formulations of N-carboxy-3-morpholinosydnone imine ethyl ester (molsidomine, Corvaton). It is applicable to dissolution data from a great variety of pharmaceutical formulations, provided that the dissolution process consists of a sequence of independent events. The model parameters are found by two different methods: by direct computation from the mean and variance of the dissolution times and by non-linear least-square parameter estimation. Both methods are compared on the basis of their resulting sum of squares (F-Test). The new pragmatic, statistical approach of data examination proves to be as effective as established routines.

Pharmacokinetic characteristics may be separated into three classes: firstly, those which are truly independent of pharmacokinetic modelling - curve characteristics for instance, such as Cmax or tmax, but also organic clearance values; secondly, those which can be evaluated without an explicit pharmacokinetic model but under basic assumptions - characteristics such as total clearance, mean and variance of residence times or total volume of distribution; and thirdly, those which are bound to elaborate pharmacokinetic models, such as hybrid constants, micro-constants or partial volumes of distribution. It can be demonstrated that the second class - the model-independent evaluated characteristic - and the third are mutually transferrable; examples of this transcription are given. However, these purely theoretical considerations can only demonstrate that the second class is consistent with classic pharmacokinetic modelling. The usefulness of the model-independent evaluated characteristic is underlined by results of clinical pharmacological investigations in which this technique was applied. The topics addressed by these studies cover the problems of deep compartments, differences in absorption, influence of disease, drug interaction, and first-pass metabolization. Since the mean-time concept in particular is still controversial in the literature, some general theoretical explanations seem to be necessary.

A new algorithm for the calculation of the mean time and further statistical moments is presented by means of a mathematical deduction which is outlined in brief. The graphical interpretation of the mathematical results demonstrates that the calculation is easy to perform. Furthermore the method is illustrated in detail with data from a sustained release formulation of theophylline. These data were obtained from a clinical study and from an in vitro dissolution test with the same formulation. Statistical analysis revealed that the rate of release in vivo was slower than in vitro by a factor of 0.7, using a commercial dissolution model. Implications of this approach with respect to in vitro - in vivo correlations are discussed.

The rotating iterative procedure (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.

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 beta 2-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.

The definition of mean residence time in the strict sense of mathematical statistics is deduced. It is demonstrated that the area-normalized concentration time curve is an estimate of the probability density function for residence times of drug molecules in the pharmacokinetic system, provided that the area under the concentration-time profile is proportional to the total amount eliminated from the system. Criticisms (8) on the determination of the mean residence time are refuted. The linearity of pharmacokinetic systems is defined, based on the statistical interpretation of these systems.

Pharmacokinetic parameters play an important part in the design of an optimal dosage schedule for a drug. These parameters are only of use to the clinician if they can be obtained reliably and without too much experimental or mathematical effort, and their predictive value is independent of elaborate pharmacokinetic models. The three cardinal parameters of clearance (CI), total volume of distribution (Vss) and mean time (T), are defined and different methods are described for their assessment in clinical practice. A more operational method for estimating T than the one recorded in the literature is recommended. The value of this new method is demonstrated by means of an evaluation of data on gentamicin from the literature which have not already been analysed pharmacokinetically, and a comparison with results obtained by classical and more costly methods.

The profile of cumulative amount released from a solid dosage form, observed in an in vitro liberation apparatus, represents the cumulative frequency of the residence times of drug molecules in the galenic formulation. The profile of release over time is usually affected by the dissolution models as well as by the experimental conditions. Such differing dissolution curves may become superimposable by a simple linear transformation of the time base. This is clearly demonstrated by two completely different retard formulations, film coated pellets and an erosible matrix tablet, which were tested in two dissolution apparatus, the Sartorius dissolution model and the USP-Paddle model. The parameters used in the transformation of the time base can be evaluated from the statistical moments of the residence times; the moments themselves are calculated from the cumulative frequency functions. The term "equivalence" of dissolution profiles is defined and discussed. The outlined considerations and methods are immediately transferable to the comparison of in vitro and in vivo liberation conditions.

It is often said that in vitro dissolution cannot reflect in vivo dissolution conditions at all, because the human body is no “beaker with stirrer”.

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.

This article reviews the published and unpublished results of pharmacokinetic studies with roxatidine acetate in healthy volunteers of different ethnic origins, patients with various degrees of renal impairment, patients on maintenance hemodialysis, lactating women, and elderly patients. In addition, it reports on the findings of interaction studies with food and other drugs. The pharmacokinetic characteristics of roxatidine were found to be nearly identical for different doses, formulations, and ethnic groups. The decrease in relative total clearance (oral clearance) in patients with renal impairment and in the elderly can be explained almost completely by their level of renal function. As expected from the pharmacokinetic characteristics in healthy volunteers, only a small amount of roxatidine is removed by hemodialysis. Dose reduction is recommended in patients with renal impairment, but dose supplementation after hemodialysis is not necessary. Only a negligible fraction of the dose administered is excreted with breast milk. No pharmacokinetic interactions were found with theophylline, warfarin, propranolol, diazepam, and desmethyldiazepam, antipyrine or antacids. Food did not interfere with the absorption or disposition of roxatidine.

Contrast media able to pass through the kidney were a major advance in the field of radiodiagnostics. Excretory urography is usually performed using metabolically-inactive substances which accumulate in the kidney and kidney-pelvis. A two-compartment model has always been used so far for pharmacokinetic evaluation of this. However, in doing so, the kidney pelvis was not taken in account. A further compartment was therefore added to this model which enables all the physiological processes demonstrated by excretory urography to be included in the evaluation. With this model, blood and urine levels can be used at the same time to calculate pharmacokinetic variables, as shown in 6 pediatric patients. In addition to the cumulative excretion of urine and blood levels of the contrast medium, the concentrations of the latter in the renal pelvis are shown. Particular attention is paid to the effects of two important factors in investigations using contrast medium--diuresis and total body fluid volume.

Drug absorption after oral administration — the most convenient and popular way of applying a drug - takes place in both the stomach and the small intestine. Little is known about the absorption characteristics of the colon.

This article reviews the published and unpublished results of pharmacokinetic studies with roxatidine acetate in healthy volunteers of different ethnic origins, patients with various degrees of renal impairment, patients on maintenance hemodialysis, lactating women, and elderly patients. In addition, it reports on the findings of interaction studies with food and other drugs. The pharmacokinetic characteristics of roxatidine were found to be nearly identical for different doses, formulations, and ethnic groups. The decrease in relative total clearance (oral clearance) in patients with renal impairment and in the elderly can be explained almost completely by their level of renal function. As expected from the pharmacokinetic characteristics in healthy volunteers, only a small amount of roxatidine is removed by hemodialysis. Dose reduction is recommended in patients with renal impairment, but dose supplementation after hemodialysis is not necessary. Only a negligible fraction of the dose administered is excreted with breast milk. No pharmacokinetic interactions were found with theophylline, warfarin, propranolol, diazepam, and desmethyldiazepam, antipyrine or antacids. Food did not interfere with the absorption or disposition of roxatidine.