PubMed Health⌕ Search

Biomedical subjects

J Heykants

Publications and source records attributed to J Heykants.

At least 55 records · Page 3Linked to original sources
PubMed1988

Pharmacokinetics of droperidol in surgical patients under different conditions of anaesthesia.

The pharmacokinetics of droperidol were studied in 42 surgical patients using doses of 5, 10 and 15 mg i.v., in association with neuroleptanalgesia or volatile anaesthetics. Plasma concentrations of droperidol were measured by radioimmunoassay. During neuroleptanalgesia, droperidol kinetics were linear over the dose range tested: the overall mean elimination half-life was 127 min, Vdss 103 litre and the plasma clearance 732 ml min-1. The kinetics of droperidol were similar under neuroleptanalgesia and under anaesthesia with halothane or enflurane. There was no significant correlation between the volume of distribution or clearance with age (14-65 yr) or body weight (48-90 kg).

Adolescent↗
PubMed1988

Alfentanil pharmacokinetics and metabolism in humans.

The metabolism of alfentanil was studied in three healthy subjects after a 1-h infusion of 2.5 mg alfentanil-3H. One of the subjects was a poor hydroxylator of debrisoquine. Pharmacokinetic parameters were similar in the three subjects and were in the same range as those reported for volunteers. The majority of the administered radioactivity was excreted in the urine (90% of the dose), but unchanged alfentanil represented only 0.16-0.47% of the dose. Alfentanil and metabolites were characterized by HPLC co-chromatography with reference compounds and/or by mass spectrometry and quantified by GLC and radio-HPLC. The main metabolic pathway was N-dealkylation at the piperidine nitrogen, with formation of noralfentanil (30% of the dose). Other Phase I pathways were aromatic hydroxylation, N-dealkylation of the piperidine ring from the phenylpropanamide nitrogen, O-demethylation, and amide hydrolysis followed by N-acetylation. Glucuronic acid conjugation of aromatic or aliphatic hydroxyl functions was the main Phase II pathway. The second major metabolite was the glucuronide of N-(4-hydroxyphenyl) propanamide (14% of the dose). The metabolite pattern in these subjects was qualitatively very similar to that described previously in rats and dogs. Differences in the mass balance of urinary metabolites between the three subjects were very small, and there was no qualitative or quantitative evidence for a deficiency in the metabolism of alfentanil in the subject who was a poor metabolizer of debrisoquine.

Alfentanil↗
PubMed1988

Hypnoanalgesia with R 8110/fentanyl in the dog: pharmacodynamic and pharmacokinetic interactions.

The pharmacokinetics and clinical effects of the short-acting hypnotic R 8110 and of the narcotic analgesic fentanyl were studied in the dog. The effects of separate intravenous (i.v.) injections of R 8110 (4 mg/kg) and fentanyl (0.015 mg/kg) and of concurrent i.v. injection of the two were studied. After administration of R 8110, induction of hypnosis occurred within 1 min, maximal depth of anaesthesia and satisfactory analgesia and muscle relaxation were obtained after 5 min. The effects had decreased within 15 min and full recovery occurred within 30 min. Fentanyl alone produced neither hypnosis nor muscle relaxation. When fentanyl and R 8110 were given simultaneously, the duration of hypnosis was doubled in comparison with R 8110 alone. Moreover, markedly improved and longer lasting analgesia and muscle relaxation were observed with the combination. When the drugs were injected together, the plasma concentrations of R 8110 were initially much higher than after separate injection of R 8110, but they became similar after 30 min. Although statistically non-significant, fentanyl reduced the total plasma clearance of R 8110 (31.1 +/- 6.9 vs. 21.9 +/- 2.3 ml/kg/min) and decreased the volume of distribution (3.78 +/- 1.83 vs. 2.23 +/- 0.90 l/kg, P less than 0.05). Fentanyl did not alter the elimination half-life of R 8110. R 8110 had no apparent influence on the pharmacokinetics of fentanyl.

Animals↗
PubMed1988

Itraconazole pharmacokinetics in patients with renal dysfunction.

The single-dose pharmacokinetics of 200 mg of oral itraconazole were studied in seven uremic patients, seven patients treated by hemodialysis, and five patients treated by continuous ambulatory peritoneal dialysis. Plasma concentration-versus-time profiles showed wide intersubject variation. This study could not demonstrate any significant effect of renal dysfunction and hemodialysis or continuous ambulatory peritoneal dialysis treatment upon the pharmacokinetics of itraconazole, and firm conclusions concerning dosing in such patients should await confirmation of our data in a larger patient population.

Administration, Oral↗
PubMed1988

Metabolism of alfentanil by isolated hepatocytes of rat and dog.

1. The biotransformation of 3H-alfentanil was studied using suspension cultures of isolated hepatocytes of male and female rats and of dogs. 2. In hepatocytes of the male rat, alfentanil was readily metabolized, following linear Michaelis-Menten kinetics over the concentration range 5-400 microM. The metabolism was strongly inhibited by the cytochrome P-450 inhibitors metyrapone, alpha-naphthoflavone and piperonyl butoxide. 3. The major metabolites of alfentanil, which were formed in suspension cultures of male rat hepatocytes, were identified by h.p.l.c. co-chromatography and by mass spectrometry and included N-[4-(hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide, N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide or noralfentanil and N-[1-[2-(4-ethyl-4,5-dihydro-5-oxo-1-H-tetrazol-1-yl)ethyl]- 4-(hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide or desmethylalfentanil. 4. The major in-vitro metabolic pathways of alfentanil in hepatocytes of the three sources were oxidative N-dealkylation at the piperidine nitrogen and oxidative O-demethylation at the methoxymethyl moiety.

Alfentanil↗
PubMed1988

Pharmacokinetics and tissue distribution of ketanserin in rat, rabbit and dog.

The plasma kinetics and tissue distribution of ketanserin [+)-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)- quinazolinedione, R 41 468) were studied in the rat, rabbit and dog. The studies were performed utilizing 3H- and 14C-labelled ketanserin and appropriate techniques to measure levels of radioactivity, unchanged drug and a major metabolite ketanserin-ol in plasma and tissues. Following intravenous administration to male rats and dogs (10 mg/kg), plasma levels could be described by a two-compartment model. The plasma clearance (C1) averaged 3.8 and 19.2 ml/min/kg and the volume of distribution (Vdss) 0.67 and 4.7 l/kg in male rats and in dogs, respectively. Following oral administration (10-40 mg/kg), ketanserin was rapidly and completely absorbed in all species studied. The absolute bioavailability of oral ketanserin was more than 80% in both rats and dogs. Due to the high clearance of the metabolites in rats, ketanserin was the main component of the plasma radioactivity. In dogs, the fraction of the metabolite ketanserin-ol was more pronounced than that of ketanserin. The apparent elimination half-life of ketanserin was 1.5 h in rabbits, 2-5 h in rats and 3-15 in dogs. The pharmacokinetics of ketanserin were dose-related after single and chronic intravenous and oral dosing. Distribution studies in rats after intravenous and oral administration (10 mg/kg) demonstrated an almost immediate equilibrium between plasma and tissues, resulting in slightly higher tissue than plasma concentrations in the well perfused tissues, and similar or slightly lower levels in the remaining tissues. Ketanserin was the main component of tissue radioactivity. The drug crossed the blood-brain barrier only to a slight extent, brain levels of the unchanged drug being similar to the free fraction in plasma. Ketanserin disappeared from tissues with a similar half-life to that in plasma. On repeated dosing, a small fraction of metabolites was more slowly eliminated. The excretion of the urinary and faecal metabolites after repeated dosing was very similar to that after a single dose. Placental transfer of ketanserin in the rat was limited. On average 0.3% of the maternal radioactive dose, preferentially metabolites, was recovered from the combined foetuses. In dogs orally treated with doses of up to 40 mg/kg/d for 12 months, no undue accumulation or retention of ketanserin or ketanserin-ol was found in any tissue. In lactating dogs orally dosed at 10 mg/kg, preferentially metabolites were excreted in the milk. Concentrations of ketanserin and ketanserin-ol in the milk were respectively 2 and 4 times higher than plasma levels.

Animals↗
PubMed1988

Pharmacokinetic evaluation of the in vitro and in vivo pharmacological profile of the major metabolites of ketanserin in the rat.

In order to explain the differences between the in vitro and in vivo pharmacological activity of two major metabolites of ketanserin [+)-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]-2,4(1H,3H)-quinazolinedione , R 41 468), viz. 6-hydroxyketanserin and ketanserin-ol, the pharmacokinetics of ketanserin and both metabolites were studied after oral and subcutaneous administration to male Wistar rats. The intrinsic potency of 6-hydroxyketanserin as a serotonin S2-antagonist is similar to that of ketanserin, as assessed by receptor-binding and pharmacological studies in vitro. In vivo, both substances are equipotent after s.c. administration, but 6-hydroxyketanserin is shorter acting and has a weak oral activity. In vitro studies indicated that ketanserin-ol is 2-3 orders of magnitude less potent than ketanserin and 6-hydroxyketanserin, but its in vivo activity is higher than could be expected from the in vitro studies. When ketanserin was administered to rats, only ketanserin and none of the metabolites was detected in plasma, indicating that the parent drug is the pharmacologically active substance. After s.c. administration of 6-hydroxyketanserin, its plasma levels decreased rapidly, explaining its short duration of action. The oral bioavailability of 6-hydroxyketanserin was very low, accounting for its low in vivo activity after oral administration. The rapid elimination and the low bioavailability of 6-hydroxyketanserin are explained by hepatic conjugation and subsequent biliary excretion. After administration of ketanserin-ol to rats, the metabolite was converted in vivo to ketanserin giving much higher plasma levels for ketanserin than for ketanserin-ol.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

Absorption, metabolism and excretion of ketanserin in man after oral administration.

The absorption, metabolism and excretion of ketanserin [+)-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)- quinazolinedione, R 41 468), a novel serotonin S2-receptor antagonist used in hypertension, was studied after a single oral dose of 14C-ketanserin tartrate in three healthy subjects. Absorption from the gastrointestinal tract was rapid and almost complete. The excretion of radioactivity amounted to about 90% after 4 days and was more abundant in urine (68%) than in faeces (24%). Ketone reduction and oxidative N-dealkylation at the piperidine nitrogen were by far the two main metabolic pathways. The former pathway resulted in ketanserin-ol, the main metabolite in plasma as well as in urine (24% of dose) and faeces (5%), the latter pathway in the urinary metabolite 1,4-dihydro-2,4-dioxo-3(2H)quinazolineacetic acid (20%). Other pathways were aromatic hydroxylation at the quinazolinedione moiety and the formation of ether glucuronides. None of the metabolites substantially contributes to the overall pharmacological activity of ketanserin. The metabolic pathways of ketanserin in man were identical to those revealed previously in rats and dogs, but the mass balance of the major metabolites resembled more that in dogs than that in rats.

Administration, Oral↗
PubMed1988

Plasma protein binding of ketanserin and its distribution in blood.

The in vitro plasma protein binding and distribution in blood of ketanserin ((+/-)-3-[2-[4-(4-fluorobenzoyl)-1- piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione, R 41 468), a novel serotonin S2-receptor antagonist used in hypertension, was studied in rats, dogs and humans. Plasma protein binding of ketanserin amounted to 95.1% in healthy subjects, 88.1% in dogs and 98.8% in rats. Its blood to plasma concentration ratio was 0.70 in humans, 0.78 in dogs and 0.65 in rats. Plasma protein binding of ketanserin-ol, the main plasma metabolite of ketanserin, was 81.2% in humans and its blood to plasma concentration ratio was 1.04. The plasma protein binding of both ketanserin and ketanserin-ol was highly dependent on pH. Albumin was by far the main binding protein for ketanserin in human plasma and binding was independent of the ketanserin concentration within a very wide range. Plasma protein binding of ketanserin in elderly hypertensive patients was not significantly different from that in healthy adults. In chronic renal failure patients, whether on haemodialysis or not, the free ketanserin fraction was 40% higher than in healthy subjects. High therapeutic levels of ketanserin (0.25 microgram/ml) did not influence the plasma protein binding of diphenylhydantoin, hydrochlorothiazide, imipramine, ketoconazole, propranolol or warfarin. Out of 12 drugs, only tolbutamide at therapeutic concentrations decreased significantly the plasma protein binding of ketanserin. However, the resulting 5-20% increase of the free ketanserin fraction is hardly clinically relevant.

Administration, Oral↗
PubMed1987

Transdermal absorption of fentanyl and sufentanil in man.

We have studied the transdermal absorption of tritiated fentanyl (citrate and base) and sufentanil citrate. Approximately 50 micrograms of drug in water was applied to the forearm skin of volunteers (5 subjects for fentanyl citrate and base, 6 for sufentanil). When the water had evaporated the site was covered with an occlusive dressing. Total urine collections were carried out for 96 h in 12 h periods. At 24 h the dressing was removed and skin removed with serial applications of adhesive tape. The radioactivity in the urine and on the tape was measured in a scintillation counter. Urine recovery expressed as a percentage of the absorbed dose was 17.9 +/- 1.9% for fentanyl citrate, 20.5 +/- 5.6% for fentanyl base, and 22.5 +/- 2.5% for sufentanil. In one subject who ran 10 miles with a sufentanil patch in situ the recovery was 52.3%. The systemic availability of fentanyl by this route is approximately 30% of that found using the intravenous route.

Administration, Cutaneous↗
PubMed1987

Interaction of miconazole, ketoconazole and itraconazole with rat-liver microsomes.

The interaction of the antimycotics miconazole, ketoconazole and itraconazole with liver microsomes from untreated rats or from rats pretreated with phenobarbital or 3-methylcholanthrene, gave rise to type II difference spectra. The interactions of the antimycotics with control, phenobarbital-induced or 3-methylcholanthrene-induced microsomes were biphasic, except for the monophasic binding of ketoconazole to phenobarbital-induced microsomes. The N-demethylation of N,N-dimethylaniline, the O-demethylation of p-nitroanisole and the hydroxylation of aniline in microsomes from untreated and inducer-treated rats were lowered by miconazole and ketoconazole, the former being the more potent inhibitor. Control microsomes were less sensitive than induced microsomes. Itraconazole was almost devoid of inhibitory properties. The three antimycotics were non-competitive (mixed) inhibitors of enzyme activities in phenobarbital-induced microsomes. The Ki values were of the same order of magnitude as the Ks values, except for itraconazole. For the latter drug, Ki values were much greater than could be expected from the spectral studies. It is concluded that the antimycotics affect microsomal enzyme activities via a direct interaction of an azole-nitrogen with the haem group of cytochrome P-450. The interaction with mammalian cytochrome P-450 decreases from miconazole greater than ketoconazole much greater than itraconazole and is much weaker than the interaction of the antimycotics with yeast cytochrome P-450.

Aniline Hydroxylase↗
PubMed1987

The metabolism and fate of closantel (Flukiver) in sheep and cattle.

Closantel was reasonably well absorbed in sheep and cattle. After oral (10 mg/kg) or parenteral (5 mg/kg) administration, similar peak times (8-48 h) and peak plasma levels (45-55 micrograms/mL) are observed. Plasma level-time curves are superimposable for either route and increase linearly with the dose. The elimination half-life of closantel is 2 to 3 weeks. The relative bioavailability of 50% of oral closantel can partly be explained by incomplete absorption. Experiments in sheep with 14C-closantel revealed that the plasma radioactivity is almost exclusively due to the unmetabolized drug, metabolites accounting for less than 2%. At least 80% of the dose was excreted with the feces over the investigational period of 8 weeks, and less than 0.5% with the urine. Closantel was only poorly metabolized. Over 90% of the fecal radioactivity was due to the parent compound. Two monoiodoclosantel isomers were the only fecal metabolites detected with radio-HPLC. The distribution of closantel to tissues was limited by its high protein binding. Closantel bound strongly (greater than 99.9%) and almost exclusively to plasma albumin. Accordingly, tissue concentrations were many times lower than the corresponding plasma levels. Residual radioactivity in sheep in all tissues but liver was entirely due to closantel. About 30% to 40% of the liver radioactivity could be attributed to monoiodoclosantel. In both sheep and cattle, residual tissue concentrations decline parallel to the plasma concentrations. Consequently, the plasma kinetics of closantel reliably reflect its depletion from tissues. Independently of the dosing scheme and route of administration, the maximum daily intake by the consumer was always below the acceptable daily intake within 4 weeks after the last dose.

Animals↗
PubMed1987

Population pharmacokinetics of alfentanil: the average dose-plasma concentration relationship and interindividual variability in patients.

The population pharmacokinetic parameters describing the plasma concentration versus time profile of alfentanil in patients undergoing general anesthesia were determined from 614 plasma concentration measurements collected in four previously reported studies with a total of 45 patients. A nonlinear regression analysis evaluating the effect of six concomitant variables revealed a significant influence of body weight on the volume of the central compartment (Vc), and a decrease with age of total body clearance (CL) and of redistribution rate from the deep compartment (k31). A small but significant effect of sex on the Vc was also observed. The duration of anesthesia and the concomitant administration of inhalational anesthetics had no effect on alfentanil pharmacokinetic parameters. The mean CL and Vc for alfentanil in a 70-kg male, aged less than 40 yr, were estimated as 0.356 l/min and 7.77 l, respectively. After correction for age, body weight, and sex, the remaining interindividual variability of alfentanil kinetics (expressed as coefficient of variation) was 48% for CL and 33% for Vc. These population pharmacokinetic parameter estimates should increase the accuracy of predicting concentration-time profiles for intravenous alfentanil infusions. A computer program is presented that allows prediction of the alfentanil plasma concentration and the 68% interval limits of the prediction from the study data analysis.

Adult↗
PubMed1987

The pharmacokinetic basis of alfentanil infusion.

Owing to the rapid blood:brain equilibration and the short duration of action, alfentanil is well suited for use in infusion techniques. A pharmacokinetic basis is given for alfentanil infusion schemes in patients undergoing routine surgery. Practical schemes can be worked out according to the general principle of a loading dose followed by a maintenance infusion. The loading dose of 100 micrograms kg-1 may be given as a short infusion, as two incremental doses, or as a combination of a single dose and short infusion. The maintenance infusion rate of approximately 1 microgram kg-1 min-1 results in steady-state plasma levels in the therapeutic range in most patients. Application of small extra doses, in addition to the maintenance infusion and modification of the infusion rate, might result in an appropriate and safe anaesthetic technique in most patients and surgical situations.

Alfentanil↗
PubMed1987

Practical aspects of alfentanil infusion.

The administration of alfentanil by infusion appears to present advantages for the induction and maintenance of anaesthesia during general surgery lasting over 1 h. The following dosage scheme is proposed: a loading dose of 100 micrograms kg-1, given either in one or two doses, or as a fast infusion administered over 10 min, followed by a maintenance infusion at a rate of 1 microgram kg-1 min-1. During maintenance anaesthesia, the infusion rate should be the lowest possible compatible with adequate analgesic effect, and should be further decreased 15-20 min before the projected end of surgery. Fine control of the opioid effect can be achieved with small increments of 7-15 micrograms kg-1 or by alterations of the alfentanil infusion rate. Breathing should be carefully monitored during the post-operative phase. Dedicated syringe pumps have been designed to avoid laborious calculations of the infusion rates and allow simple, rapid changes of the infusion rate.

Alfentanil↗
PubMed1987

Pharmacokinetics and tissue distribution of the new gastrokinetic agent cisapride in rat, rabbit and dog.

The plasma kinetics and tissue distribution of the gastrokinetic (+/-)-cis-4-amino-5-chloro-N-[1-(3-(4-fluorophenoxy)propyl]-3-methoxy-4- piperidinyl]-2-methoxybenzamide monohydrate (cisapride, R 51 619) have been studied in the rat, rabbit and dog. After intravenous administration to rats (5 mg/kg) and dogs (0.63 mg/kg) plasma level-time curves were adequately fitted to a two-compartmental model. The plasma clearance (ClT) and volume of distribution (Vdss) averaged 91 ml/min.kg and 4.7 l/kg in the rat and 4.2 ml/min.kg and 0.82 l/kg in the dog, respectively. Following oral administration, cisapride was rapidly and almost completely absorbed from the gastrointestinal tract in rats and rabbits. The absorption was somewhat slower in the dog. In male rats the plasma radioactivity was mainly due to metabolites, unaltered cisapride representing on average 10% of the total radioactivity. A markedly larger proportion of the parent drug was seen in female rats. Linear plasma kinetics were observed for cisapride in the dose range of 10 to 160 mg/kg. Similarly in the dog, linearity was observed after oral administration in the range of 0.31 to 10 mg/kg. The plasma kinetics remained unaltered on repeated oral doses of 10 mg/kg to rats and subchronic intravenous administration at 0.63 mg/kg to dogs. Compared with intravenous administration, the absolute bioavailability of oral cisapride was 23% in rats and 53% in the dog for the drug given in solution. The terminal plasma half-life of cisapride was about 1-2 h in the rat and about 4-10 h in the rabbit and dog.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗