More on sublingual flunarizine.
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Biological Availability↗
Biomedical subjects
J Heykants
Publications and source records attributed to J Heykants.
Electrophysiologic, antiarrhythmic and hemodynamic effects of transcainide.
Transcainide was selected as an antiarrhythmic drug with potential clinical application. In isolated dog, sheep and rabbit Purkinje fibres, in dog and guinea-pig trabecular preparations and in the guinea-pig right auricle, transcainide decreases the rate of rise of the transmembrane action potential, with no effect on normal spontaneous activity and calcium-mediated action potentials; it inhibits early after-depolarizations. The effect on the rate of rise is very slow in onset. In vivo a prolongation of QRS duration is observed. In dogs, the drug is effective against post-infarction and ouabain-induced ventricular arrhythmias, and abolishes acetylcholine and aconitine-induced atrial fibrillation; it elevates the threshold of electrically induced ventricular fibrillation. Hemodynamic studies in anaesthetized and unaesthetized dogs indicate that transcainide moderately decreases contractility, while slightly increasing frequency. No major side effects are seen. Preliminary data on the pharmacokinetics suggest that in the dog the observed effects after i.v. infusion are related to the parent drug. Transcainide is an antiarrhythmic of the local anaesthetic type, with very slow kinetics. It is characterized by a good oral absorption and a long duration of action.
Action Potentials↗
Bioavailability of three oral dosage forms of cisapride, a gastrointestinal stimulant agent.
Relative bioavailability of the investigational gastrointestinal stimulant agent cisapride after oral administration was determined in healthy men. Treatments administered were (A) two 5-mg tablets; (B) one 10-mg tablet; (C) 10 mL of a 1-mg/mL suspension; and (D) 10 mL of a 1-mg/mL aqueous reference solution. The study had a randomized four-way, crossover design; drug administration was followed by a standard breakfast. Plasma cisapride concentrations in blood samples drawn over 48 hours were measured by high-performance liquid chromatography. Individual and mean values for bioavailability parameters were subjected to analysis of variance followed by multiple comparison testing. Time to maximum concentration was shortest after administration of the solution. There was a significant difference in mean peak plasma concentrations between treatment A (48.8 +/- 12.8 ng/mL) and treatment D (41.6 +/- 10.6 ng/mL), with treatment A producing a 17.3% higher peak concentration. No significant differences between treatments were found for area under the plasma concentration-time curve. The overall mean elimination half-life was 7.01 hours. The results of the study indicate that the tablet and suspension dosage forms of cisapride are bioequivalent to the reference solution.
Administration, Oral↗
Induction potential of antifungals containing an imidazole or triazole moiety. Miconazole and ketoconazole, but not itraconazole are able to induce hepatic drug metabolizing enzymes of male rats at high doses.
Male Wistar rats were dosed with miconazole, ketoconazole and itraconazole by gastric intubation once daily for up to 7 days. A dose- and time-dependent induction of the hepatic drug metabolizing enzyme system was observed for miconazole and ketoconazole, while itraconazole proved to be devoid of inductive properties even at the highest dose studied (160 mg/kg). No effect on drug metabolizing enzymes could be demonstrated for either drug at a dose level of 10 mg/kg, which is just above the antifungally active dose. At a dose of 40 mg/kg, miconazole, but not ketoconazole, significantly increased cytochrome P-450 content. At the highest dose of 160 mg/kg, both miconazole and ketoconazole increased the relative liver weight, the cytochrome P-450- and b5-content and NADPH-cyt c-reductase. Furthermore, miconazole, but not ketoconazole, increased specific microsomal aminopyrine and N,N-dimethylaniline N-demethylase activity, p-nitroanisole O-demethylase activity and UDP-glucuronyltransferase activity towards 4-nitrophenol while the specific aniline hydroxylase activity was unaffected. Ketoconazole at 160 mg/kg only induced O-demethylase activity and UDP-glucuronyltransferase activity, while it lowered the specific activities towards the other substrates. Miconazole was a relatively more potent inducer when compared to ketoconazole. Both drugs displayed biphasic effects on the mixed-function oxidase activities, which were lowered after acute administration (160 mg/kg, 1 hr before death) and were induced when determined after 23 hr had elapsed or after multiple dosage. Both drugs bound strongly to their respective induced cytochromes, giving rise to type II difference spectra, and inhibited the O-demethylase activity of the induced microsomes with an I50 of 5.2 microM for miconazole and 15.1 microM for ketoconazole. On the basis of a comparison of the enzymatic activities induced by both antimycotics with those induced by PB or 3-MC, it was concluded that miconazole behaved as a PB-type inducer, whereas ketoconazole did not belong to either category of inducers. A comparison of electrophoretograms of microsomes from different origins on SDS-PAGE revealed that miconazole increased the concentration of several proteins, whereas ketoconazole selectively induced a protein with Mr of 47,800. The protein pattern in the 50 kDa region of miconazole-induced microsomes resembled that of PB-microsomes qualitatively.
Aniline Hydroxylase↗
Protein binding of the analgesics alfentanil and sufentanil in maternal and neonatal plasma.
Maternal and umbilical venous plasma was obtained at delivery from 8 mothers and their neonates after an i.v. bolus injection of alfentanil, and from 6 mothers and their neonates after epidural administration of sufentanil. Plasma levels of total (free + bound) alfentanil in neonates were about 3.4-times lower than in their mothers. At 33-55 min after 30 micrograms sufentanil, total drug levels in mothers were around the limit of detection of the radioimmunoassay (0.05 ng/ml); in one mother who had received 250 micrograms, the plasma level of total sufentanil was 2.6-times higher than in her neonate. Plasma protein binding of alfentanil was 88.2% in mothers and 67.2% in neonates. Plasma protein binding of sufentanil was 90.7% in mothers and 79.3% in neonates. For both drugs, plasma protein binding was significantly related to the alpha 1-acid glycoprotein (alpha 1-AGP) level, which was about 2.5-times lower in the infants. Free alfentanil levels in mothers and neonates were similar. Free levels of sufentanil in mothers and neonates differed less from each other than did the total drug levels.
Alfentanil↗
Alfentanil kinetics in renal insufficiency.
Alfentanil 100 micrograms/kg was administered as an i.v. bolus to 9 patients with severe chronic renal dysfunction (creatinine clearance 1.0 +/- 1.2 ml/min) requiring regular haemodialysis. Plasma alfentanil concentrations were measured by a specific radioimmunoassay. Individual plasma concentration-time curves were fitted to a two-compartment open model. Mean distribution and elimination half-lives were 3.7 min and 58 min, respectively. The apparent volumes of distribution of the central compartment and the total volume of distribution at steady-state were 91 ml/kg and 304 ml/kg, respectively. Alfentanil plasma clearance was 5.3 +/- 2.5 ml/min/kg. All the patients tolerated alfentanil well and no side-effects nor delayed recovery were observed.
Adult↗
Pharmacokinetic approach to equilibrium between ketanserin and ketanserin-ol.
The metabolic reduction-oxidation equilibrium between ketanserin and ketanserin-ol was studied after oral dosing of both substances to two healthy volunteers. Comparison of plasma Cmax and AUCs indicated that the equilibrium was shifted towards ketanserin-ol. There is evidence that ketanserin-ol elimination is the slowest step dictating the terminal half-life of ketanserin.
Administration, Oral↗
Pharmacokinetics of ketanserin and its metabolite ketanserin-ol in man after intravenous, intramuscular and oral administration.
The pharmacokinetics of ketanserin (R 41 468), a novel serotonin S2-receptor blocking agent widely investigated for its effect on acute and chronic hypertension, has been studied in 10 healthy male subjects. They received single 10 mg doses i.v. and i.m., and 20, 40 and 60 mg solutions of ketanserin by mouth, in a five-way cross-over design. The model-independent kinetics of i.v. ketanserin were characterized by a terminal half-life of 14.3 +/- 4.4 h, a moderate plasma clearance (CL = 565 +/- 57 ml/min) and a large tissue distribution (Vss = 268 +/- 71 l, Vz = 703 +/- 204 l; mean +/- SD). Following i.m. administration, peak levels of nearly 200 ng/ml were attained within 10 minutes and the absolute bioavailability was 112 +/- 23%. After oral dosing, peak levels of ketanserin were reached within 1 h. The peak level and AUC increased in proportion to the dose. The absolute bioavailability was 46.8, 50.4 and 55.5% for 20, 40 and 60 mg doses and they conformed to the predicted bioavailability based on i.v. clearance data. The terminal half-life of 17 h and the urinary excretion of parent drug (about 0.7% of the dose) were similar after oral and parenteral dosing. The kinetics of ketanserin-ol, the major metabolite of ketanserin formed by ketone reduction, was also studied. Because of its negligible pharmacological activity, the contribution of ketanserin-ol to the overall therapeutic effect of ketanserin is small, in spite of its 1.6-times (parenteral) to 3.2-times (oral) higher plasma level than that of ketanserin.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Itraconazole pharmacokinetics in the female genital tract: plasma and tissue levels in patients undergoing hysterectomy after a single dose of 200 mg itraconazole.
Twenty patients who underwent hysterectomy received a single dose of 200 mg itraconazole at different moments before surgery. At the moment of surgery, a urine sample, blood sample and tissue samples of different organs of the female genital tract were collected. Blood levels and tissue levels of itraconazole were measured by means of an HPLC method. Itraconazole blood levels were lower than the corresponding tissue levels in the various organs of the female genital tract. This finding for itraconazole is different from findings with ketoconazole, indicating that itraconazole has a higher affinity for tissue than ketoconazole. Urine levels of itraconazole were virtually undetectable in all samples. None of the patients complained of side-effects, and blood biochemical parameters all remained within the normal limits. The premedication with itraconazole had no effect whatsoever on the induction and maintenance of and recovery from the anaesthesia. No abnormal effects on ECG were observed.
Adult↗
Reliability of sufentanil plasma level assays in patients.
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Anesthetics↗
Pharmacokinetics and dose proportionality of ketoconazole in normal volunteers.
Ketoconazole is an orally effective, broad-spectrum, systemic antifungal agent. The pharmacokinetics and bioavailability of ketoconazole given as a 200-mg single dose in a tablet, suspension, or solution were studied in 24 fasting healthy males by using a crossover design. Levels of ketoconazole in plasma were determined for up to 48 h by a sensitive reverse-phase high-performance liquid chromatography method. The absorption of ketoconazole was rapid, with mean maximum concentrations of the drug in plasma of 4.2, 5.0, and 6.2 micrograms/ml attained at 1.7, 1.2, and 1.0 h, respectively, after administration of the tablet, suspension, and solution, respectively. The mean distribution and elimination half-life values were 1.5 to 1.7 and 7.5 to 7.9 h, respectively. The mean oral clearance of the solution dose was 209 (+/- 82.9 [standard deviation]) ml/min, and the mean apparent volume of distribution was 88.31 (+/- 68.72) liters. The relative bioavailabilities for the tablet and suspension were 81.2 (+/- 33.5) and 89.0 (+/- 23.1)%, respectively, of that of the solution. The data indicated the bioequivalence of the tablet to the suspension and of the suspension of the solution. Dose proportionality of ketoconazole was also studied in 12 volunteers after they received solution doses of 200, 400, and 800 mg. Linear correlations between the dose and the maximum concentration of the drug in plasma, the time to the maximum concentration, and the area under the concentration-time curve were observed. However, the increase in the area under the curve was more than proportional to the dose given. The levels in plasma seemed to decay at a lower rate after 400- and 800-mg doses. The mean oral clearance decreased from 244.9 to 123.6 and 80.0 ml/min, respectively, as the dose increased from 200 to 400 and 800 mg. The apparent dose-dependent kinetics may have been due to the presystemic elimination and capacity-limited hepatic metabolism which become saturated at higher doses.
Administration, Oral↗
Plasma concentrations of astemizole in patients with terminal renal insufficiency, before, during and after hemodialysis.
Four patients undergoing hemodialysis because of terminal renal insufficiency have taken 10 mg of astemizole on two consecutive days. The elimination was followed for 7 days and was found not to be delayed. During dialysis no decrease of the plasma levels of astemizole and its hydroxylated metabolites were observed. On the contrary, a small nonsignificant increase was found which can be explained by the thickening of the blood after ultrafiltration. It can be concluded that astemizole cannot be eliminated by dialysis because of its high protein binding capacity.
Adult↗
Potential of interaction between the H1-antagonist astemizole and other drugs.
Astemizole is a potent H1-antagonist devoid of sedative effects, which was found at single oral daily doses to be very effective in the treatment of allergic rhinitis, allergic conjunctivitis, and urticaria. Its interaction potential on other drugs was studied in various ways. Studies on salivary antipyrine clearance, the 6-beta-hydrocortisol excretion, the elimination rate of ethanol and the indocyanine-green clearance are presented. No changes were observed. Astemizole also was given in combination with diazepam or alcohol. Psychomotor performance failed to show any effects. In none of these studies was there any evidence of interaction of astemizole on other drugs. This review summarizes the data available thus far.
Animals↗
The use and limitations of deuterated lorcainide in metabolism and pharmacokinetic studies.
Lorcainide, a new antiarrhythmic agent currently undergoing clinical trial, has been pentadeuterated and the usefulness of this labelled compound in pharmacokinetic and metabolism studies has been investigated in dogs. Specific analytical methods based on capillary gas chromatography/mass spectrometry (GC/MS) were developed for quantitative and qualitative analysis of plasma and urine samples. Following oral administration of an equimolar mixture of 5 : 5 mg of (2H0/2H5)lorcainide, eight major metabolites were rapidly identified in urine by the ion cluster technique. Quantitative analysis of (2H0/2H5)lorcainide in plasma and urine indicated an enhanced systematic availability of the deuterated compound, probably due to a secondary isotope effect. According to these findings in the dog, the use of deuterated lorcainide in human bioavailability and metabolism studies is probably of limited value.
Animals↗
Alfentanil kinetics in the elderly.
Alfentanil disposition after an intravenous bolus of 50 micrograms/kg was followed in 15 elderly surgical patients and was compared to that in nine young adults. A two-compartment open model described alfentanil disappearance from plasma. Apparent volumes of distribution of the central compartment (201 and 211 ml/kg; means), at steady state (460 and 543 ml/kg), and of the AUC (746 and 722 ml/kg) in young adults and in elderly subjects did not differ. Plasma clearance was lower in elderly subjects (4.4 ml/min/kg) than in young adults (6.5 ml/min/kg), whereas terminal plasma t1/2 was longer in the elderly patients (137 and 83 min). Alfentanil dosage should therefore be reduced in elderly patients when large single doses, multiple doses, or long-term infusions are required.
Adult↗
Plasma levels, biotransformation and excretion of oxatomide (R 35 443) in rats, dogs and man.
Plasma levels, biotransformation and excretion of oxatomide were studied after single oral doses of 14C-oxatomide in male rats, dogs and humans. Oxatomide was very well absorbed, and almost completely metabolized in the three species. Excretion of the metabolites was very rapid and complete within a few days; the 14C label was excreted more in the faeces (54-62%) than in the urine (27-40%). Major metabolic pathways of oxatomide were oxidative N-dealkylations at the piperazine nitrogens and at the benzimidazolone nitrogen in rats and man, and also aromatic hydroxylation at the benzimidazolone moiety in man. The main urinary metabolite in the three species was 2,3-dihydro-2-oxo-1H-benzimidazole-1-propanoic acid, resulting from the oxidative N-dealkylation at the 1-piperazine nitrogen.
Adult↗
Overview of the clinical pharmacokinetics of alfentanil.
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Adolescent↗
Simultaneous determination of astemizole and its demethylated metabolite in animal plasma and tissues by high-performance liquid chromatography.
A high-performance liquid chromatographic procedure has been developed for the determination of astemizole and its primary metabolite in plasma and animal tissues. Both compounds and the internal standard were extracted from alkalinized plasma with heptane--isoamyl alcohol and analyzed using a reversed-phase column and UV monitoring at 254 nm. The detection limits for both compounds were 1 ng/ml of plasma and 5 ng/g of tissue and extraction recoveries were sufficiently high (71-84%). The method was applied to plasma and tissue samples from dogs after repeated oral administration, and to plasma samples from a volunteer taking a 300-mg oral dose of the drug. The results were compared with those obtained by a formerly developed radioimmunoassay.
Animals↗