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Biomedical subjects

J Heykants

Publications and source records attributed to J Heykants.

At least 91 records · Page 5Linked to original sources
PubMed1983

Bioavailability and saturation of the presystemic metabolism of oral lorcainide therapy initiated in three different dose regimens.

The feasibility of giving a supplementary starting dose of the antiarrhythmic drug lorcainide, in order to minimalize the impact of the extensive, but saturable first-pass metabolism, was evaluated. Twenty-five adult patients were given 100 mg lorcainide tablets according to one of 3 different dosage schedules: Eight patients took one tablet at 0, 12 and 24 h, 8 took 1 tablet at 0, 1, 12 and 24 h and 9 took 1 tablet at 0, 2, 12 and 24 h. Levels of lorcainide and its metabolite, nor-lorcainide, during treatment were determined by gas-liquid chromatography. The results show that giving a second tablet 1 or 2 h after the first may produce faster saturation of the pre-systemic metabolism of lorcainide in the liver.

Aged↗
PubMed1983

Pharmacokinetics of the infusion of alfentanil in man.

The pharmacokinetics of alfentanil under the conditions of an empirically derived 1-h continuous infusion of 3 micrograms kg-1 min-1, with a bolus of 80 micrograms kg-1, both i.v., were determined in five patients. The distribution half-life (mean +/- SD) (7.4 +/- 3.1 min), elimination half-life (86.7 +/- 15.8 min), apparent volume of distribution, Varea (0.44 +/- 0.15 litre kg-1) and elimination clearance (3.33 +/- 0.75 ml kg-1 min-1) were similar to those previously reported for a single bolus of alfentanil. These values for apparent volume of distribution and clearance can be used to calculate correct bolus and infusion doses to maintain any desired steady state plasma concentration using standard formulae: for example, to maintain a steady state plasma concentration of 400 ng ml-1, a bolus dose of 176 micrograms kg-1 and an infusion of 1.3 micrograms kg-1 min1 would be required.

Adult↗
PubMed1983

Radioimmunoassay of the new opiate analgesics alfentanil and sufentanil. Preliminary pharmacokinetic profile in man.

The development of two analogous radioimmunoassay (RIA) procedures based on dextran-charcoal separation is described for the quantification of two fentanyl-like analgesics, alfentanil and sufentanil. Immunization of rabbits with conjugates of bovine serum albumin and carboxy-derivatives of the respective drugs resulted in the production of antisera capable of detecting less than 0.05 ng ml-1 of the parent analgesics with high specificity and almost no cross-reactivity with major metabolites. Excellent agreement was obtained between RIA--without prior extraction--and gas chromatography for alfentanil concentrations in human plasma. Because of sufentanil's low therapeutic plasma levels, no comparison could be made between its RIA and an alternative assay, however, there was strong evidence for the specificity of the assay when applied directly to plasma. With these RIA methods preliminary information was obtained on plasma concentrations and elimination of alfentanil or sufentanil in patients given an intravenous bolus injection of 50 micrograms kg-1 of alfentanil, or 5 micrograms kg-1 of sufentanil. For both analgesics, the pharmacokinetic profile in man could be described by a three-compartment model. The terminal elimination half-life was 88 min for alfentanil and 140 min for sufentanil. Six hours after a therapeutic dose, plasma levels were in the order of 3 and 0.3 ng ml-1 for alfentanil and sufentanil respectively.

Alfentanil↗
PubMed1983

Excretion and metabolism of flunarizine in rats and dogs.

The excretion and metabolism of (E)-1-[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-propenyl)piperazine dihydrochloride (flunarizine hydrochloride, R 14 950, Sibelium) were studied after single oral doses in rats and dogs, using tritium-labelled as well as 14C-labelled drug. Flunarizine was well absorbed in both species. The mass balance for the unchanged drug and its major metabolites in urine, bile and faeces, as estimated with radio-HPLC, ALLOWED an explanation of the differences observed for the excretion pattern of the radioactivity in flunarizine-14C and flunarizine-3H dosed rats, and in male and female rats. Main metabolic pathway in male rats was the oxidative N-dealkylation resulting in bis(4-fluorophenyl)methanol and a number of complementary metabolites of the cinnamylpiperazine moiety, of which hippuric acid was the main one. In female rats and male dogs, however, hydroxy-flunarizine was the main metabolite, resulting from the aromatic hydroxylation of the phenyl ring of the cinnamyl moiety. Enterohepatic circulation of bis(4-fluorophenyl)methanol and hydroxy-flunarizine was proved by "donor-acceptor" coupling in rats; in bile and urine, these two metabolites were present mainly as glucuronides. The glucuronide of hydroxy-flunarizine was also the main plasma metabolite in dogs.

Animals↗
PubMed1982

Sensitive gas chromatographic method for the determination of cinnarizine and flunarizine in biological samples.

A sensitive method has been developed for the determination of the vasoactive compounds cinnarizine and flunarizine in plasma, urine and milk samples from man and animals. The procedure involves the extraction of the drugs and their internal standard from the biological samples at alkaline pH, back-extraction into sulphuric acid and re-extraction into the organic phase (heptane-isoamyl alcohol). The analyses were carried out by gas chromatography using a nitrogen-selective thermionic specific detector. The detection limit was 0.5 ng/ml of biological fluid and extraction recoveries were sufficiently high (87-94%). The method was applied to plasma samples from bioavailability studies of both cinnarizine and flunarizine in healthy volunteers, and to plasma, urine and milk samples from flunarizine-treated dogs.

Animals↗
PubMed1982

The pharmacokinetics of alfentanil (R39209): a new opioid analgesic.

The pharmacokinetics of alfentanil (R39209), a new short-acting opioid analgesic, have been studied in eleven patients. Six patients were given 50 micrograms/kg alfentanil and five patients 125 micrograms/kg as an intravenous bolus injection. Plasma concentrations were measured at intervals up to 6 h (50 micrograms/kg) or 8-10 h (125 micrograms/kg), using a specific radioimmunoassay technique. Plasma concentrations declined triexponentially in both groups. The initial elimination of alfentanil from the plasma was very rapid with 90% of the administered dose leaving the plasma within 30 min. The average half-lives for the three phases were similar for both groups. The combined mean (+/- SEM) half-lives for the 11 patients for the rapid and slow distribution phases were short (t 1/2 pi = 1.2 +/- 0.26 min, t 1/2 alpha = 11.6 +/- 1.63 min). The elimination half-life, t 1/2 beta was 94 +/- 5.87 min which is considerably shorter than that of other opioids. The mean (+/- SEM) total body clearance was 6.4 +/- 1.39 ml . kg-1 . min-1 and the volume of distribution (Vd) was 0.86 +/- 0.194 l/kg. The latter is considerably less than reported values for the chemically related drug, fentanyl, and suggests that alfentanil may have a lower tissue binding affinity than fentanyl. The rapid elimination and short duration of clinical action suggests the feasibility of repeated administration of alfentanil and its use by continuous intravenous infusion.

Adult↗
PubMed1982

Pharmacokinetics of alfentanil in man.

The distribution and elimination kinetics of alfentanil, a new short-acting analgesic, were studied in five surgical patients. Its behavior, following a bolus injection of 120 micrograms/ml, was compatible with a three-compartment open-model distribution. The disappearance of the drug from plasma was rapid (t 1/2 pi = 3.5 +/- 1.3 minutes, t 1/2 alpha = 16.8 +/- 6.4 minutes) with 96.4% of the drug eliminated from plasma in 1 hour, indicating extensive transfer to the remote peripheral compartment. This was followed by a slower elimination phase with a t 1/2 beta of 94 +/- 38 minutes. Total volume of distribution was 1.03 +/- 0.50 L/kg. Total plasma clearance was 456 +/- 155 ml/min. The short analgesic effect of this drug might be attributed to the rapid displacement of the drug from the central and intermediate compartments to the remote peripheral compartment. Approximately 25% of the injected dose was present in the remote peripheral compartment 30 to 60 minutes after alfentanil administration. As the return of drug from this peripheral to the central compartment is slower than the elimination rate of the drug, it could be the rate-limiting step in the elimination of alfentanil from the body.

Alfentanil↗
PubMed1982

The pharmacokinetics of mebendazole and flubendazole in animals and man.

A sensitive and specific radioimmunoassay procedure was developed for mebendazole and flubendazole enabling a more thorough study of the systemic absorption and pharmacokinetic behaviour of the drugs. In rats, plasma levels of oral and subcutaneous mebendazole were about 10 times higher than those of flubendazole. The pro-drug R 34 803 showed levels of metabolically formed flubendazole similar to those found for mebendazole. Intramuscular flubendazole in dogs, injected for 5 consecutive days, produced sustained fairly high plasma levels for at least 6 weeks after the last dose. The absorption of oral flubendazole in man was markedly enhanced when the drug was taken together with a meal. A 20-times higher dose, however, produced only an increase by 1.4 of the plasma levels and AUC-values, indicating that the absorption of flubendazole is limited by the extremely poor solubility of the drug in the contents of the gastrointestinal tract.

Animals↗
PubMed1981

Determination of levamisole in plasma and animal tissues by gas chromatography with thermionic specific detection.

A rapid and sensitive method has been developed for the determination of the anthelmintic levamisole in plasma and tissues from man and animals. The procedure involves the extraction of the drug and its internal standard from the biological material at alkaline pH, back-extraction into sulphuric acid and re-extraction into the organic phase (heptane-isoamyl alcohol). Several extraction steps can be omitted, however, whenever the gas chromatographic background permits and some operations can be simplified using Clin ElutTM extraction tubes. The analyses were carried out by gas chromatography using a nitrogen-selective thermionic specific detector. The detection limit was 5 ng, contained in 1 ml of plasma or in 1 g of the various tissues, and recoveries were sufficiently high (79-86%). The method was applied to human plasma samples in a comprehensive bioavailability study of levamisole in healthy volunteers, and to plasma and tissues in a residue trial in cattle. The effect of the blood collection technique on the plasma levels was also studied and pointed to decreased plasma concentrations when Vacutainer tubes were used.

Animals↗
PubMed1981

On the pharmacokinetics of domperidone in animals and man. I. Plasma levels of domperidone in rats and dogs. Age related absorption and passage through the blood brain barrier in rats.

Domperidone, a novel gastrokinetic and antinauseant lacking central side-effects, was administered intravenously to male Wistar rats and orally to fasted rats of either sex and to 1- and 6-day old neonates at doses of 2.5 mg 14C-labelled drug/kg. The biphasic absorption of domperidone in fasted rats was extremely rapid suggesting a partial absorption from the stomach. The metabolism of domperidone was sex- and age-related: it was slower in the female rat and in the neonates. The elimination system for the metabolites was still immature in the 1-day old pups. The distribution of domperidone (and related metabolites) to the rat brain was limited, brain concentrations being lower than corresponding plasma levels in all cases. In 1-day old neonates, the blood-brain barrier was less obstructive to the passage of domperidone than in older rats. In Beagle dogs, domperidone pharmacokinetics were described by a two-compartment model with half-lives of distribution and elimination of 6 minutes and 2.45 hours respectively. The time-courses of the drug plasma levels were similar for single and repeated (once daily for 11 months) doses of 2.5, 10 and 40 mg/kg, indicating that chronic administration of domperidone, even at high dose levels, did not alter its pharmacokinetics. AUC-values increased proportionally with the dose pointing to linear pharmacokinetics over a wide dose range.

Age Factors↗
PubMed1981

On the pharmacokinetics of domperidone in animals and man II. Tissue distribution, placental and milk transfer of domperidone in the Wistar rat.

Tissue distribution, placental transfer and transition into milk of the gastrokinetic drug domperidone were studied in the Wistar rat after i.v. or p.o. administration of the labelled compound at 2.5 mg/kg. Whole-body autoradiography and liquid scintillation counting were used to investigate the tissue localization of domperidone in pregnant and non-pregnant rats. In fasted rats, tissue levels were maximal within 15 minutes after either route. In non-fasted animals peak time occurred 30 minutes after oral treatment. Large amounts of radioactivity were present in the stomach, and in the bilious contents of the intestine. High activity was further detected in the liver, kidney, lung and some glandular tissues. After a rapid initial decrease radioactivity was eliminated with a half-life of 8-10 hours. Except for brain and testes, plasma levels were markedly lower than corresponding tissue levels. At 1 hour placental levels were 2-2.7 times higher and foetal concentrations 2.1-2.5 times lower than maternal plasma levels. The placentae and foetuses predominantly contained unchanged domperidone. At peak time only 0.2 (i.v.) and 0.08% (p.o.) of the dose crossed the placenta. Blood levels were always lower than milk concentrations. Preferentially metabolites were excreted with the milk. After a 20-hour suckling period of orally dosed dams, 0.2% of the dose was recovered in the combined tissues of 6 suckling pups.

Administration, Oral↗
PubMed1981

On the pharmacokinetics of domperidone in animals and man III. Comparative study on the excretion and metabolism of domperidone in rats, dogs and man.

The excretion and metabolism of the novel gastrokinetic and antinauseant drug domperidone were studied after oral administration of the 14C-labelled compound to rats, dogs and man, and after intravenous administration to rats and dogs. Excretion of the radioactivity was almost complete within four days. In the three species, the radioactivity was excreted for the greater part with the faeces. Biliary excretion of the radioactivity amounted to 65% of the dose 24 hours after intravenous administration in rats. Unchanged domperidone as determined by radioimmunoassay, accounted in urine for 0.3% in dogs, 0.4% in man, and in faeces for 9% in dogs and 7% in man. The main metabolic pathways of domperidone in the three species were the aromatic hydroxylation at the benzimidazolone moiety, resulting in hydroxy-domperidone -the main faecal metabolite-, and the oxidative N-dealkylation at the piperidine nitrogen, resulting in 2,3-dihydro-2-oxo-1H-benzamidazole-1-propanoic acid the major radioactive urinary metabolite- and 5-chloro-4-piperidinyl-1,3-dihydro-benzimidazol-2-one. In urine the two first metabolites were present partly as conjugates. A mass balance for the major metabolites in urine, faeces, bile and plasma samples was made up after radio-HPLC (reverse-phase HPLC with on-line radioactivity detection) of various extracts. Only minor species differences were detected.

Adult↗
PubMed1981

On the pharmacokinetics of domperidone in animals and man. IV. The pharmacokinetics of intravenous domperidone and its bioavailability in man following intramuscular, oral and rectal administration.

The pharmacokinetics and bioavailability of domperidone, a novel gastrokinetic, were studied in healthy male subjects by comparing plasma concentrations and urinary excretion following intravenous, intramuscular, oral and rectal administration. Two oral dosage forms were studied: 10-mg tablets and a 10-mg/ml oral solution. The influence of a meal on the oral bioavailability and the dose-proportionality were also investigated. Plasma levels of intravenous domperidone could be described by a three-compartment model with a rapid distribution of 40% of the dose to a "shallow" peripheral compartment. The final elimination half-life was 7.5 hours. Peak plasma levels were reached within 30 minutes following intramuscular and oral administration and at 1-4 hours following rectal administration. Since domperidone showed an extensive first-pass elimination, AUC-values -a measure for the bioavailability- were considerably lower after oral than after parenteral administration. Equal oral and rectal doses gave a similar bioavailability. AUC-values increased proportionally with the dose over a 10-60 mg range. Cumulative urinary excretion of unchanged domperidone was proportional to corresponding AUC-values. The bioavailability was discussed in the light of the therapeutic results.

Administration, Oral↗
PubMed1980

Serum haloperidol determinations in psychiatric patients. Comparison of methods and correlation with serum prolactin level.

Twenty-one serum samples from 11 schizophrenic patients receiving long-term haloperidol therapy were analyzed for haloperidol concentrations by two different radioimmunoassays (RIAs) and gas chromatography (GC). There was a good correspondence between the RIA and GC values over a wide range of drug concentrations. However, compared with the specific GC technique, both RIA methods overestimated haloperidol concentrations, reflecting differences in the specificities of the two RIA antibodies. One of the RIA methods had the requisite specificity for application to patients treated with long-term haloperidol therapy, although further methodological refinement will be required for its general clinical application. Haloperidol values determined by GC and RIA analyses correlated highly with prolactin concentrations in the same samples, suggesting that the usefulness of prolactin measurement as an "in vivo bioassay" for circulating levels of haloperidol should be further explored.

Chromatography, Gas↗