Search PubMed⌕ Search

Biomedical subjects

T W Guentert

Publications and source records attributed to T W Guentert.

At least 37 records · Page 2Linked to original sources
PubMed1990

Biopharmaceutical evaluation of ketoprofen following intravenous, oral, and rectal administration in dogs.

The influence of the hydrophilicity of three suppository bases on the rectal absorption of ketoprofen was studied. Absorption characteristics of ketoprofen were compared after intravenous, oral, and rectal administrations of 100 mg of drug given in a crossover design to five dogs. Rectal formulations included an aqueous solution and three suppository formulations. After oral dosing, ketoprofen was rapidly absorbed (time of maximum concentration, tmax: 0.83 +/- 0.61 h), and a comparison with the intravenous solution indicated a complete bioavailability of 0.90 +/- 0.10. After rectal administration, the rate of absorption, as evaluated with tmax and mean absorption time, was always slower than after oral dosing. A high variability was observed in the plasma concentrations obtained with suppository formulations; bioavailability values were approximately 20% lower than those from the oral solutions. No statistical difference in bioavailability and peak concentrations between the three suppository formulations was observed. Time of peak concentrations, mean absorption times, and fractions of the dose absorbed 6 h post administration did not show a difference in rate of ketoprofen absorption from the three suppository formulations. This study did not reveal a relationship between rate and extent of ketoprofen rectal absorption and the hydrophilicity of the suppository bases tested.

Administration, Oral↗
PubMed1990

Pharmacokinetic study of doxifluridine given by 5-day stepped-dose infusion.

Doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUR) metabolism has been reported to be saturable and associated with a fall in clearance of the drug as the dose is increased. The aim of the present study was to determine the disposition of 5'-dFUR and 5-fluorouracil (5-FU) when 5'-dFUR was given as a 5-day infusion, with the infusion rate increased stepwise every 24 h. Measurement of plasma and urinary levels of 5'-dFUR and 5-FU at steady state for each infusion rate enabled the estimation of 5'-dFUR renal (ClR) and nonrenal (ClNR) clearance and 5-FU renal clearance. A total of 28 patients with histologically proven malignancy received 5-day courses of 5'-dFUR ranging in dose from 3.75 to 20 g/m2 per 120 h. The lowest dose given over 24 h was 0.25 g/m2, and the highest was 5 g/m2. Steady-state plasma levels of 5'-dFUR ranged from 167 to 6,519 ng/ml. At these plasma levels there was no evidence of significant saturation of 5'-dFUR metabolism; steady-state plasma levels of 5'-dFUR increased approximately linearly with dose, and nonrenal clearance did not change significantly with dose. There was also no evidence of nonlinearity in 5'-dFUR renal clearance. The mean (+/- SD) ClR of 5'-dFUR was 108.9 +/- 53.6 ml/min per m2 (range, 45.7-210 ml/min per m2), and the ClNR was 728 +/- 181 ml/min per m2 (range, 444-1,119 ml/min per m2). Renal clearance comprised 13% of the total 5'-dFUR clearance. The mean renal clearance of 5-FU was 100.8 +/- 48.6 ml/min per m2 (range, 23.5-198 ml/min per m2). There was considerable interpatient variability in 5'-dFUR renal and nonrenal clearance, even at the same dose level. We concluded that the administration of 5'-dFUR by the infusion method described avoided the saturation of nonrenal elimination processes reported to occur with shorter infusion schedules.

Adult↗
PubMed1990

Binding of drugs in milk: the role of casein in milk protein binding.

Unbound fractions of 14C-labeled diazepam and tenoxicam in skimmed milk of various species (man, horse, goat, cow, sheep, dog, rabbit) with different milk compositions were determined. Furthermore, the protein binding of five 14C-labeled benzodiazepines differing in their lipophilicity (bromazepam, clonazepam, diazepam, flumazenil, and flunitrazepam) were measured in human milk and in artificially prepared solutions of individual milk proteins (lactoferrin, 2.4 g/liter; alpha-lactalbumin, 2.1 g/liter; albumin, 0.4 g/liter; and casein--2.1, 3.4, and 13.3 g/liter). The extent of binding was determined by equilibrium dialysis of protein solution against 1/15 M phosphate buffer, made isocryoscopic with lactose. The results showed that the casein fraction is a major binding component in milk for all tested drugs. The extent of binding of diazepam and tenoxicam in the milk of various species was independent of the whey protein concentration. In human milk the fraction of bromazepam, clonazepam, diazepam, and flunitrazepam bound to casein was higher than that bound to any other of the milk proteins tested. Albumin contributed little to the overall binding of these benzodiazepines, and lactoferrin and alpha-lactalbumin did not account for significant binding. The benzodiazepine antagonist flumazenil showed the lowest overall binding in milk and in casein solution. As the casein concentration is highest in colostral milk and drops during the course of lactation, it is expected that M/P ratios of drugs strongly bound to casein are higher during the first days postpartum than in later phases of lactation.

Albumins↗
PubMed1990

A phase I study of doxifluridine as a five-day stepped-dose continuous infusion.

Doxifluridine (5'-dFUR) is a prodrug of 5 fluorouracil (5-FU) synthesized in an attempt to improve the therapeutic index compared with 5-FU. In this phase I study, cohorts of three patients were treated by a 5-day continuous infusion with the dose increased daily, total doses ranging from 3.75 g/m2 to 20 g/m2/120 h. Twenty-nine patients received 54 courses (median 2, range 1-4). The dose-limiting toxicities were mucositis (Miller grade 3 in three patients and grade 4 in another) and grade 4 neutropenia and thrombocytopenia in two patients. Other toxicities included nausea, vomiting, and diarrhea, rash, and fever. Neurological toxicity was mild and no cardiovascular toxicity was recorded. Plasma and urine levels of 5'-dFUR and 5-FU were quantitated by high-performance liquid chromatography. Steady-state plasma levels between 167 ng/ml and 6,519 ng/ml were recorded and at these levels there was no evidence of saturation of doxifluridine metabolism. One patient at the maximum tolerated dose of 20 g/m2/120 h had a complete response in a nasopharyngeal carcinoma.

Adult↗
PubMed1990

Biotransformation of moclobemide in humans.

The structure of the urinary metabolites formed after moclobemide administration in human was elucidated, and the pattern compared with that in the plasma. The metabolic pathways of moclobemide were also compared with those of structurally related substances. After oral moclobemide administration, on average 95% of the dose was recovered in the urine within 4 days, with a mean of 92% being excreted during the first 12 h. The drug is extensively metabolized: less than 1% of the dose was excreted unchanged. A total of 19 metabolites, accounting together for about 64% of the dose, was isolated and all metabolites accounting for more than 1% of the dose were identified. Consistent with other morpholine-containing compounds, metabolic pathways of moclobemide include mainly oxidative attack on the morpholine moiety, leading to a multitude of oxidation products. Four primary metabolic reactions were identified: morpholine N-oxidation, aromatic hydroxylation, morpholine C-oxidation and deamination. The major metabolites in urine are 4 carboxylic acids (M7A and M7B, M8, M9) that account for 49% of the dose. Only 2 metabolites (M3, M10) were found to be hydroxylated on the aromatic nucleus. They were excreted completely as conjugates of glucuronic and/or sulfuric acid. Conjugation in general, however, seems to be of minor importance in the overall biotransformation of the drug. The metabolite pattern in plasma was found to be qualitatively but not quantitatively similar to that observed in urine. Almost all of the main urinary metabolites were found in plasma as well. The unchanged parent compound and 2 primary oxidation products of the morpholine ring (M1, M15), which were present in urine only in trace amounts, could easily be detected in plasma.

Administration, Oral↗
PubMed1990

Pharmacokinetics of moclobemide after single and multiple oral dosing with 150 milligrams 3 times daily for 15 days.

This study was undertaken to determine the absolute bioavailability and steady-state concentrations of moclobemide after doses of 150 mg. In 14 healthy human volunteers, no differences in tmax, t 1/2 beta, C1/F, Cmax and AUC were found between a single oral dose of 100 mg and one of 150 mg. The mean absolute oral availability was 0.66 and 0.69 respectively. Plasma concentration profiles of moclobemide on repeated dosing with 150 mg 3 times daily for 15 days were essentially superimposable, although the mean concentration was higher than after the single 150 mg dose. This concentration increased over the first week and then remained relatively constant. Mean accumulation factors for moclobemide during the first week were 1.85 for Cmax and 3.0 for AUC. These values were higher than predicted from single-dose characteristics. There was a marked reduction in the variability of AUC and clearance (C1/F) values at steady-state compared with the first dose. Minimum plasma concentrations of the 2 metabolites, Ro 12-5637 and Ro 12-8095, were relatively stable throughout dosing. The exact mechanism of the decrease in systemic and oral clearance of moclobemide with time during multiple oral dosing is not known at present. Either moclobemide inhibits its own clearance or moclobemide metabolism is inhibited by one or more of its metabolites. The findings indicate that, if dosage needs to be adjusted during treatment with moclobemide, the changes should be made carefully and at intervals of not less than 1 week.

Administration, Oral↗
PubMed1990

Absorption and disposition of moclobemide in patients with advanced age or reduced liver or kidney function.

Three different studies were conducted to assess the pharmacokinetics of moclobemide in subjects with conditions complicating dose determination. The first examined the absorption and disposition of moclobemide in an elderly population and compared these with results obtained in a group of normal young subjects. No significant differences were found between the groups in the intravenous (i.v.) parameters of disposition, and no differences with regard to disposition of the metabolite, Ro 12-8095. In addition, the minimum steady-state concentrations of moclobemide and the main plasma metabolite did not differ between the elderly and younger patients. In the second study, clearance tests in patients with cirrhosis of the liver confirmed that hepatic function is drastically reduced in this group of patients; it is therefore possible that moclobemide absorption and distribution might be influenced. In only 3 of the 12 patients investigated, slowly declining plasma concentrations after administration pointed to a severely limited elimination capacity for moclobemide. In the remaining 9 subjects, average values of several parameters changed significantly (t 1/2 beta, MRT and C1), whereas Vss and renal clearance were not significantly altered. In patients with kidney dysfunction, there were no differences in kinetics between patients undergoing hemodialysis and those who were not. Compared with normal healthy volunteers, no differences were found for renal patients, with the exception of the mean absorption time, which was significantly prolonged. From these studies it can be concluded that, pharmacokinetically, neither age nor renal impairment require adjusting the dosage of moclobemide. Patients with liver cirrhosis, however, need to have the usual dose reduced to one half or one third, or else the dosage intervals can be increased to prevent cumulation.

Administration, Oral↗
PubMed1990

Comparison of the pharmacokinetics of moclobemide in poor and efficient metabolizers of debrisoquine.

A number of pharmacokinetics studies in which patients had been phenotyped and poor metabolizers for moclobemide found were analysed retrospectively. There were 27 subjects in all, aged between 19 and 75 years, and 5 of these were classified as poor debrisoquine metabolizers. Although there was a wide variability in the pharmacokinetic parameters observed, no consistent relationship was found between these and debrisoquine phenotype. Poor debrisoquine metabolizers all had values within the extremes for the efficient metabolism. This was true for both single and multiple dosing. This analysis is limited by the small number of subjects as well as its retrospective nature. Nevertheless, the data suggest that no deviations of moclobemide pharmacokinetics should be expected in poor metabolizers of debrisoquine compared with normal metabolizers.

Adult↗
PubMed1990

Increase of plasma nonesterified fatty acid concentration and decrease of albumin binding affinity after intravenous injection of glycocholate-lecithin mixed micelles.

Lipophilic drugs intended for intravenous use can be solubilized by mixed-micellar systems containing glycoholic acid and lecithin (MM). Our present studies determined the influence of such MM preparations on albumin binding of monoacetyldiaminodiphenyl sulfone (MADDS), a deputy ligand for bilirubin. After intravenous administration of MMs to healthy male and female adult volunteers, concentration-time profiles of bile acid and nonesterified (NEFA) and esterified fatty acids were obtained as well. In vitro experiments with blood from adults and from neonatal cords indicated a modest reduction in reserve albumin for binding of MADDS after addition of MMs, resulting from glycocholic acid in the micellar preparation. After injection of MM preparations with up to 530 mg glycocholic acid, a rapid decrease of the reserve albumin was observed. The effect was more pronounced in men than in women and resulted in different areas under the time curve for the decrease (p = 0.049). At their maximum (3 to 10 minutes after MM doses) the decreases averaged (+/- SD) 68% +/- 14% in men and 45% +/- 8.5% in women. Low reserve albumin concentrations were maintained over 20 minutes despite rapidly declining bile acid concentrations. Injection of MM caused a drastic increase of NEFA in the serum samples with a more pronounced effect in men (average +/- SD increase: 473% +/- 93%) than in women (148% +/- 91%) (p = 0.01). The changes in NEFA concentrations ran reciprocal to the changes of reserve albumin for binding MADDS. In all subjects the increase in NEFA was accompanied by a decrease in reserve albumin for palmitate. Fatty acid binding to albumin was well restored within 1 hour. Thus, before drugs incorporated in MM can be prescribed to neonates who are at risk for having kernicterus, the impact of intravenous MM on bilirubin binding and NEFA levels must be investigated in that patient population.

Adult↗
PubMed1989

Effects of alpha-interferon on theophylline pharmacokinetics and metabolism.

1. The influence of alpha-interferon (Roferon-A) on the pharmacokinetics and metabolism of theophylline was studied in healthy adults. Roferon-A was administered as an intra-muscular injection (3 x 10(6) iu) once-a-day over 3 days. One week prior to and immediately after this course a single 20 min aminophylline infusion (4 mg kg-1) was given. 2. Blood samples for theophylline analysis were taken over 48 h. Urine was collected up to 72 h and assayed for theophylline and its major metabolites 3-methylxanthine, 1,3-dimethyluric acid and 1-methyluric acid. 3. Pharmacokinetic parameters for theophylline in plasma were calculated. From urinary excretion data the overall metabolic clearance of theophylline and clearances for formation of the metabolites were calculated. 4. After interferon administration, there was a significant increase of approximately 15% in the mean values of the terminal elimination half-life, area under the curve and mean residence time of theophylline in association with a similar decrease in plasma clearance (P less than 0.05). Formation clearances of the metabolites tended to be smaller after treatment, but only the change in the overall clearance of theophylline was significantly different (P less than 0.05). There was no systematic shift in the metabolic pattern of theophylline. 5. Additional investigations of the influence of the duration of alpha-interferon treatment are necessary before definite conclusions can be drawn about the mechanism and the clinical relevance of the described interaction.

Adult↗
PubMed1989

Effect of age on the pharmacokinetics of tenoxicam in comparison to other non-steroidal anti-inflammatory drugs (NSAIDs).

Investigations have shown that elderly patients have an increased sensitivity to the effects of non-steroidal anti-inflammatory drugs (NSAIDs) with a concomitant higher frequency of side-effects. Several explanations for such an observation are possible including altered receptor responsiveness or changes in absorption and disposition of a drug. From a literature survey it becomes clear that the rate and extent of NSAID absorption do not appear to be changed to a clinically significant degree in the elderly patient. Most NSAIDs are eliminated predominantly by hepatic metabolism and metabolic clearance therefore controls their elimination and accumulation upon chronic dosage. Differences in the dependence of these disposition processes on age exist between the commonly used NSAIDs. In our studies with tenoxicam, steady-state concentrations and accumulation factors did not differ in elderly subjects from those observed in a young population. Therefore, no dosage adjustment of this drug is necessary in elderly patients to achieve similar plasma concentrations following standard dosing in young subjects. Disposition processes of propionic acid derivatives seem to be more affected by advanced age as shown by reports in the literature. Alterations in plasma protein binding, with an increased free fraction of the drug subsequent to changes in serum albumin concentrations were reported with naproxen and salicylates in the aged population. Similarly, ketoprofen and ibuprofen clearance were significantly lower in the elderly than in young volunteers, and an accumulation of naproxen was reported in the elderly after multiple dosing.

Adult↗
PubMed1989

[Pharmacokinetics and metabolism of reversible MAO-A inhibitors in the human].

Monoamine oxidase (MAO) type A inhibitors are used as antidepressants. A number of drug candidates in this therapeutic class are currently being evaluated clinically. The objective of the present review is to evaluate the pharmacokinetics of five MAO-A inhibitors (moclobemide, toloxatone, brofaromine, cimoxatone, amiflamine). Differences between these drugs exist in their absorption and disposition characteristics. However, a detailed comparison reveals a strong similarity between moclobemide and toloxatone (high hepatic extraction ratio; reduced oral bioavailability due to first-pass metabolism; similar binding to plasma protein, fb approximately 0.23). Elimination half-lives of 1-3 h for moclobemide and toloxatone contrast with the higher values for amiflamine (5-12 h), cimoxatone (9-16 h) and brofaromine (12-15 h). All five MAO-A inhibitors undergo complete hepatic elimination, and only a negligible fraction of the dose (less than 1%) is excreted unchanged in the urine. Oxidation represents the major degradation pathway. Results from studies in populations with increased risk factors are scarce for the discussed MAO-A inhibitors except for moclobemide. For this drug it has been shown that neither age nor reduced kidney function influence plasma levels significantly. Liver insufficiency reduces the body's elimination capacity for moclobemide. As a consequence similar doses result in higher plasma concentrations in liver impaired patients than subjects with normal hepatic function and a dose adjustment may therefore become necessary.

Antidepressive Agents↗
PubMed1989

The pharmacology of reversible monoamine oxidase inhibitors.

The older monoamine oxidase inhibitors (MAOIs) are mechanism-based, irreversible inhibitors of MAO; most inhibit both the A and B forms of MAO. Several of the drugs are hydrazine derivatives which have non-specific effects other than MAO inhibition. These properties convey disadvantages, which may be seen as serious, though infrequent, adverse events--the 'cheese effect', hepatotoxicity, amphetamine-like activity, orthostatic hypotension and anticholinergic effects. New, reversible MAOIs stem from a variety of chemical classes and are more specific in their effects, with relatively rapid onset of action, direct relationship between plasma concentration and pharmacological effect, and no prolonged carry-over phenomena.

Administration, Oral↗
PubMed1988

The influence of cholestyramine on the elimination of tenoxicam and piroxicam.

We have studied the influence of multiple oral doses of cholestyramine on the single dose pharmacokinetics of tenoxicam and piroxicam in eight healthy young volunteers. Each subject received on two occasions single intravenous injections of 20 mg tenoxicam and on another two occasions single oral doses of 20 mg piroxicam. Both medications were followed by multiple oral doses of either cholestyramine or plain water (placebo). Compared with placebo cholestyramine accelerated the elimination of both drugs. The average values of half-lives were reduced (tenoxicam: 31.9 h vs 67.4 h; piroxicam: 28.1 h vs 46.8 h) due to increases in clearance. Cholestyramine-mediated enhancement of drug elimination was most pronounced in the subjects with a comparatively low baseline drug clearance. Thus, intersubject variability in clearance was smaller when the drug administrations were followed by the anion-exchange resin. The twofold acceleration of tenoxicam elimination in the present study in man contrasts with a much larger effect (five-fold) seen in experiments with dogs. This points to a much easier access of unchanged tenoxicam to the intestinal lumen in the dogs than in man. Comparing the pharmacokinetics of tenoxicam and piroxicam in the same volunteers revealed a high degree of correlation in clearance and half-lives and similar intersubject variabilities in mean kinetic variables.

Adult↗
PubMed1987

Pharmacodynamics of 3-hydroxyquinidine alone and in combination with quinidine in healthy persons.

The relation between serum concentration of 3-hydroxyquinidine (3-OHQ), a major metabolite of quinidine in humans, and the pharmacologic effect alone and in combination with the parent drug was studied. The heart rate-corrected, computer-averaged QT interval (QTc) was used as the pharmacologic endpoint. In a randomized, double-blind study, 5 healthy subjects received, on 3 separate days 1 week apart, either (1) 300 to 400 mg 3-OHQ orally or (2) 150 mg quinidine base intravenously or (3) a combination in the same doses. Blood samples and electrocardiographic recordings were obtained over the following 10 hours. Serum concentrations of 3-OHQ and quinidine were determined by high-pressure liquid chromatography and the free fraction by ultrafiltration. Peak concentrations of 3-OHQ varied between 1,362 and 3,480 ng/ml after oral 3-OHQ ingestion, but were negligible after intravenous quinidine infusion. The free fraction was 49% +/- 4.8 (mean +/- standard deviation) for 3-OHQ and 20% +/- 4.3 for quinidine. In all 5 subjects a statistically significant correlation was found between serum concentration and QTc prolongation for both quinidine and 3-OHQ (largest p value less than 0.025). The mean slope of the regression line was 0.0184 +/- 0.0128 for 3-OHQ and 0.0297 +/- 0.0111 for quinidine. Multiple linear regression revealed in each subject a significant additive effect of 3-OHQ when administered together with quinidine (largest p value less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Kinetics and dynamics of quinidine-N-oxide in healthy subjects.

The pharmacokinetics of a major metabolite of quinidine in humans, quinidine-N-oxide, were investigated after single oral doses (3 to 15 mg) in four healthy subjects. The concentration in serum and urine was determined by an HPLC assay. Because of a small volume of distribution, the elimination half-life of quinidine-N-oxide was only 2.5 +/- 0.28 hours (mean +/- SD), considerably shorter than that of quinidine. The renal clearance was 1.3 +/- 0.3 L/hr. Only 13.9% +/- 3.7% of the dose was recovered in urine as unchanged compound for up to 12 hours. Two unidentified compounds with the same retention time as quinidine and 3-hydroxyquinidine were found in the urine samples of two subjects. The free fraction in serum was 3.3% +/- 0.83%. No systematic changes in heart rate-corrected QT interval were observed up to concentrations of 500 ng/ml. The results indicate that quinidine-N-oxide, in contrast to 3-hydroxyquinidine, does not possess quinidine-like pharmacologic activity.

Administration, Oral↗
PubMed1987

Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

Mixed micelles (MM) formed from glycocholic acid and lecithin are suited to solubilize lipophilic drugs for intravenous use. To test for possible drug-drug interactions, the protein binding of a series of agents known to bind to different sites on albumin (diazepam, warfarin, ketoprofen, frusemide, probenecid) and additionally (prazosin, quinidine, propranolol) or exclusively (disopyramide) to alpha 1-acid glycoprotein or to transcortin (prednisolone) was determined in the presence and absence of MM. Concentrations of MM, corresponding to the maximum possible plasma concentration achieved by injecting the highest clinical doses of MM into the systemic circulation, had little or no effect on the unbound fractions of drugs known to bind exclusively to albumin. Only at five times higher MM concentrations were the free fractions substantially increased (by up to 45%). Unbound fractions of drugs bound with high affinity but low capacity to alpha 1-acid glycoprotein were increased between 50-85% even at 'therapeutic' doses of MM. The present study suggests that drugs solubilized by MM should be given by slow injection or infusion to patients already receiving drugs which are highly bound to alpha 1-acid glycoprotein.

Glycocholic Acid↗