Drugs recently released in Belgium: mitoxantrone, gemfibrozil.
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Biomedical subjects
Publications and source records attributed to C Harvengt.
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The relative and absolute bioavailability of different oral forms of amiodarone was examined in 12 subjects. The doses were 5 mg/kg iv, two 200-mg commercial tablets by mouth, two 200-mg tablets (new formulation) by mouth, and 400 mg in a drinkable solution. Plasma levels of amiodarone and its N-desethylated metabolite were determined by HPLC. Statistical analysis indicated bioequivalence of the oral forms for all the kinetic parameters examined. After oral dosing, amiodarone was slowly absorbed and the maximum plasma level (0.55 +/- 0.20 mg/l) was reached in 4.5 hr. The absolute bioavailability of oral amiodarone was calculated by comparison of AUCs after oral dosing with those after intravenous injection. A mean oral bioavailability of 65% +/- 22% was indicated. Since the tablets were bioequivalent to the drinkable solution, incomplete absorption seems not be a result of the dissolution characteristics of the commercial formulation but rather of a first-pass effect.
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Intralipid is a fat emulsion which is widely used for intravenous nutrition in very ill patients. In order to know more about the capacity of these patients to metabolize exogenous triglycerides, the plasma activities of lipoprotein lipase (LPL), hepatic lipase (HL) and lecithin: cholesterol acyltransferase (LCAT), the key enzymes in the metabolism of serum lipoproteins were measured by a radioisotope technique in 23 critically ill patients and 20 patients with recent major surgery. Compared with normal volunteers, the activities were significantly decreased. On the other hand, the capacity to clear intravenously given Intralipid (0.1 g/kg), expressed as fractional removal rate (K2), was retained in patients. It is suggested that the measurement of K2 could not be useful to evaluate the capacity of Intralipid administration to satisfy the metabolic needs and also that its utilization must be reevaluated in terms of potential harmful effects.
The influence of administration of cimetidine (1 g daily for 2 weeks) on the pharmacokinetics of alprazolam (0.5 mg t.i.d. for 1 week) and triazolam (0.5 mg nightly for 1 week) was investigated in two groups of 8 healthy subjects. The plasma AUC of these triazolobenzodiazepines were significantly increased. Moreover, for triazolam, the C max was increased and the plasma elimination half-life was prolonged; oral clearance of the two triazolobenzodiazepines was markedly reduced. It is suggested that the combined treatment cimetidine-alprazolam requires a reduced daily dosage (one third) of alprazolam or increased dosage intervals (b.i.d. instead of t.i.d.). For triazolam, used as a hypnotic drug, such dosage reduction appears unsuitable if administered on a once-nightly basis.
Hamsters were given a diet containing fenofibrate (0.5% or 0.05%) or its metabolite, LF 2151 (0.15% or 0.015%) or a standard diet for a 3-week period. At the end of this period, the analysis of plasma lipids showed that the mean plasma triglyceride concentrations were not significantly different in the five groups of animals. The mean plasma cholesterol concentrations were significantly reduced in animals treated with both drugs but only when given at the high dosage. No consistent changes were noted in the liver weight/body weight ratio and the DNA content of the liver; the number of peroxisomes was increased in the hepatocytes of animals given fenofibrate at the high dosage. Liver homogenates were fractionated and the fractions rich in peroxisomes were used for assays of several enzymes involved in lipid metabolism. Compared with the control animals, activity of cyanide-insensitive fatty acyl-CoA (FA-CoA) oxidizing system was significantly increased by fenofibrate at the high dosage, carnitine acetyltransferase activity was markedly increased by both drugs at the high dosage and catalase activity remained unmodified. As there was a significant inverse correlation between the peroxisomal activity of FA-CoA oxidizing system and the plasma cholesterol concentrations, it is suggested that the increase of peroxisomal beta-oxidation activity can be involved in the hypocholesterolemic action of fenofibrate and LF 2151. This is further substantiated by the finding that fenofibrate and LF 2151 were present in the peroxisomal fraction only in hamsters displaying hypocholesterolemia and high activity of FA-CoA oxidizing system. The presence of fenofibric acid in the plasma of hamsters given LF 2151 suggested that hepatocytes are able to generate the parent drug from this metabolite, underlining that the pharmacokinetics of fenofibrate are rather complex in hamsters.
The plasma kinetics of mitoxantrone (MX), a new cytostatic anthracenedione, were investigated with HPLC in five leukemic patients suffering from acute myeloid leukemia, at the dose of 24 mg m-2 infused over 30 min at constant rate. The decay of the plasma concentrations was best fitted to a three compartment model with average elimination half-lives of respectively 4.1 min (alpha-phase), 19.8 min (beta-phase) and 8.9 h (gamma-phase), a mean distribution volume of 317 l m-2 and an average total body clearance of 0.37 l min-1 m-2. The cumulative urinary recovery of unchanged MX was 7.5% of the administered dose in 4 days, with the highest elimination during the first day. No MX urinary metabolites or conjugates have been detected.
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